IndraLab

Statements

"Finally, we observed that nucleotide excision repair (NER) components (e.g., XPC, XPA, ERCC1) were up-regulated by USP35-FUCA1 axis, indicating a potential mechanism for USP35-FUCA1-mediated platinum resistance in CRC."

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"Therefore, we performed a series of functional studies under the regulation of USP35-FUCA1 axis, aiming to better understand the role of FUCA1 in cancers."

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"Finally, we suggested that USP35-FUCA1 axis up-regulated nucleotide excision repair (NER) components (e.g., XPC, XPA, ERCC1), which could be a potential mechanism for platinum resistance in CRC."

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"To validate our screened results, we first examined whether the physical interaction existed between USP35 and FUCA1."

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"As illustrated in Fig. xref , USP35 interacted with FUCA1 in a reciprocal fashion."

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"The interaction between endogenous USP35 and FUCA1 was also detected in LoVo and DLD-1 cells (Fig. xref )."

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"As p53 mutation was found in approximately 60% of the CRC patients [ xref ], we specifically focused on exploring the role of USP35-FUCA1 axis in p53 mutant DLD-1 and HT29 cells."

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"To explore the role of USP35-FUCA1 axis in vivo, we subcutaneously inoculated the control (EV + shNC), USP35-overexpressed (USP35 + shNC), and USP35 overexpressed FUCA1-depleted (USP35 + shFUCA1-4) HT29 cells in the athymic nude mice, intraperitoneally injected water (H 2 O), single drug (OXA as a representative), or combined drugs (OXA + 5-FU) weekly into the mice, and routinely monitored the tumor growth."

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"Next, we examined the USP35-FUCA1 axis in the human CRC tissues."

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"Therefore, these results suggest that USP35 expression correlates well with FUCA1 expression in CRC patient samples, and USP35-FUCA1 axis contributes to CRC tumor growth and chemo-resistance in vivo."

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USP35 deubiquitinates FUCA1.

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"We found that only the catalytically active USP35 (USP35 WT), not the USP35 mutant (USP35 C450A), deubiquitinated FUCA1 (Fig. 4A)."

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"We further confirmed that FUCA1 was deubiquitinated and stabilized by USP35."

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"Overall, this study indicates that USP35 contributes to tumorigenesis and confers chemo-resistance in CRC by deubiquitinating FUCA1, unraveling a novel molecular target for CRC treatment."

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"USP35 deubiquitinates and stabilizes FUCA1."

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"Considering USP35 is a deubiquitinase, we then investigated whether FUCA1 was deubiquitinated by USP35."

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"Overall, these results demonstrate that USP35 deubiquitinates FUCA1 and increases FUCA1 stability by preventing ubiquitin-proteasome pathway-mediated degradation of FUCA1."

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Mutated USP35 deubiquitinates FUCA1. 1 / 1

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"We found that only the catalytically active USP35 (USP35 WT), not the USP35 mutant (USP35 C450A), deubiquitinated FUCA1 (Fig. 4A)."

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USP35 activates FUCA1.

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"In parallel with the in vitro data, USP35 overexpression weakened drug-induced cell apoptosis while knockdown of FUCA1 in USP35-overexpressed cells restored drug-induced cell apoptosis, suggesting that USP35 contributes to OXA/5-FU resistance through stabilizing FUCA1 in vivo (Fig. 6D and S13A–C)."

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"We found that overexpression of wild-type USP35 (USP35 WT), not the catalytically inactive mutant USP35 (USP35 C450A), prevented FUCA1 from degradation in LoVo cells, whereas knockdown of USP35 accelerated FUCA1 degradation in DLD-1 cells (Fig. 4C, D)."

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"Resultantly, enhanced USP35 expression increased FUCA1 at protein levels in CRC cells and HEK293T in a dose dependent manner (Fig. S6A, B), while dampened USP35 expression clearly decreased the protein levels of FUCA1 in DLD-1 and HCT116 cells (Fig. S6C)."

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"USP35 promotes cell proliferation and chemotherapeutic resistance through stabilizing FUCA1 in colorectal cancer."

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USP35 decreases the amount of FUCA1.

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USP35 decreases the amount of FUCA1. 2 / 2

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"As shown in Fig. 5A, FUCA1 expression was reduced to approximately the basal levels by FUCA1-specific shRNA-4 in the USP35-overexpressed LoVo and HT29 cells."

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USP35 inhibits FUCA1.

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USP35 inhibits FUCA1. 1 / 1

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"In addition, to investigate the involvement of the NER pathway in USP35-mediated chemo-resistance, we silenced XPA in USP35-depleted FUCA1-overexpressed DLD1 cells using XPA-specific siRNA and examined cell apoptosis in response to chemotherapeutics by flow cytometry analysis."

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USP35 affects MAVS

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USP35 binds MAVS.

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"Taken together, these results suggest that USP35 interacts with MAVS both in vivo and in vitro, and this interaction is regulated by viral stimulation."

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"To investigate the mechanism how USP35 inhibits the RIG-I-MAVS pathway, we examined the interaction between USP35 and MAVS."

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"Reciprocal Co-IP assay displayed that endogenous USP35 could bind to endogenous MAVS (Fig. 3D, E)."

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"To validate whether USP35 directly interacts with MAVS, we performed a GST Pull-down assay using the purified USP35 protein and detected a direct interaction between GST-USP35 and MAVS (Fig. 3F)."

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"To explore whether the binding of USP35 to MAVS is regulated by VSV virus stimulation, we infected cells with the VSV virus."

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"The interaction between USP35 and MAVS was enhanced in a time-dependent manner following VSV treatment (Fig. 3C)."

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"To identify the domains involved in the binding of USP35 to MAVS, we constructed a series of truncations of MAVS."

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"USP35 directly binds to MAVS and removes the K63-linked polyubiquitin chain of MAVS, a process dependent on the enzyme activity of USP35."

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"USP35 interacts with MAVS in vivo and in vitro."

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"To investigate the mechanism how USP35 inhibits the RIG-I-MAVS pathway, we examined the interaction between USP35 and MAVS."

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USP35 binds MAVS and K63. 1 / 1

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"USP35 directly binds to MAVS and removes the K63-linked polyubiquitin chain of MAVS, a process dependent on the enzyme activity of USP35."

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USP35 inhibits MAVS.

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"Deubiquitination enzyme USP35 negatively regulates MAVS signaling to inhibit anti-tumor immunity."

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"These results suggest that USP35 inhibits MAVS activity to restrain type I interferon production."

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"These results suggest that USP35 negatively regulates MAVS activity, thereby restraining type I interferon production."

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"Here, we report that the ubiquitin-specific protease 35 (USP35) negatively regulates the MAVS signaling."

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USP35 deubiquitinates MAVS.

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"In contrast, both USP35-WT and USP35-CA had no significant effect on the ubiquitination of RIG-I or TBK1 (Fig. 4B, C), indicating that USP35 specifically deubiquitinates MAVS."

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"Moreover, the knockdown of USP35 promoted the ubiquitination of endogenous MAVS (Fig. 4E)."

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"The ubiquitination experiments showed that USP35-WT, but not catalytically inactive USP35-C450A mutant could deubiquitinate MAVS (Fig. 4A)."

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USP35 activates cell population proliferation.

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"In vitro knockdown of USP35 suppresses KIRC cell proliferation, migration, and EMT."

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"Ectopic USP35 expression in cancer cells inhibited cell proliferation, while silencing USP35 induced proliferation in vitro."

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"USP35 depletion could decrease PRAD cell proliferation rates relative to parental control cells that could be restored by USP35 overexpression, as suggested by the cell viability assays (Fig. 2D)."

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"Colony formation assays revealed that silencing USP35 led to a significant decrease in the number of colonies formed by KIRC cells, indicating reduced cell proliferation (Fig. 8B)."

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"The results demonstrated that USP35 knockdown with siRNAs remarkably reduced cell proliferation and survival ability (Fig. S6 A-C), whereas overexpression of USP35 promoted cell proliferation and survival (Fig. S6 D-F), which is consistent with the findings that USP35 can promote mitotic progression 30.To further investigate whether the enzymatic activity of USP35 is required for its biological effects, we transfected GC cells with a WT-USP35 vector or USP35-C450A mutant (Fig. 5A) and performed Transwell and scratch wound healing assays."

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"Collectively, these data indicated that USP35 promotes the proliferation, migration, and stemness properties of PRAD cells both in vitro and in vivo."

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"It has been shown that USP35 overexpression enhances CRC cell proliferation and resistance to oxaliplatin and 5-FU[85]."

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"Upregulation of USP35 promotes CRC cell proliferation and imparts resistance to both oxaliplatin and 5-Fu."

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"We also verified that USP35 promotes the proliferation and survival of GC cells, which is consistent with certain findings reported previously 30."

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"Knockdown of USP35 causes reduced proliferation, cell cycle arrest, increased apoptosis, and mitigated migration and invasion of HCC cells."

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USP35 inhibits cell population proliferation.

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"Ectopic USP35 expression in cancer cells inhibited cell proliferation, while silencing USP35 induced proliferation in vitro."

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"MTT results showed that overexpression of USP35 inhibited cell proliferation significantly compared with their respective controls in both H1299 and LNCaP cells."

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"MTT results showed that overexpression of USP35 inhibited cell proliferation significantly compared with their respective controls in both H1299 and LNCaP cells (Figure xref )."

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"We then determined the roles of USP35 and found that overexpression of USP35 could inhibit cancer cell proliferation in vitro and tumorigenesis in vivo."

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"USP35 inhibits cancer cell proliferation."

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"USP35 activated by miR let-7a inhibits cell proliferation and NF-kappaB activation through stabilization of ABIN-2."

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"USP35 inhibits cancer cell proliferation."

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"USP35 overexpression inhibited cell proliferation in vitro and inhibited xenograft tumor growth in vivo."

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"Taking together, these results suggested that USP35 is an inhibitor of proliferation in cancer cells both in vitro and in vivo."

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"Liu and colleagues have reported that USP35 inhibits cell proliferation via suppression of NF-kappaB activation by deubiquitination and stabilization of ABIN-2 (Liu C et al (2015) Oncotarget 6, 27891-27906)."

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FUCA1 affects USP35

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FUCA1 binds USP35.

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"Therefore, we performed a series of functional studies under the regulation of USP35-FUCA1 axis, aiming to better understand the role of FUCA1 in cancers."

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"Finally, we suggested that USP35-FUCA1 axis up-regulated nucleotide excision repair (NER) components (e.g., XPC, XPA, ERCC1), which could be a potential mechanism for platinum resistance in CRC."

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"To validate our screened results, we first examined whether the physical interaction existed between USP35 and FUCA1."

36864055

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"As illustrated in Fig. xref , USP35 interacted with FUCA1 in a reciprocal fashion."

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"The interaction between endogenous USP35 and FUCA1 was also detected in LoVo and DLD-1 cells (Fig. xref )."

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"As p53 mutation was found in approximately 60% of the CRC patients [ xref ], we specifically focused on exploring the role of USP35-FUCA1 axis in p53 mutant DLD-1 and HT29 cells."

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"Next, we examined the USP35-FUCA1 axis in the human CRC tissues."

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FUCA1 activates USP35.

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"Hence, our finding that FUCA1 mediates the function of USP35 on cell proliferation and chemo-resistance in CRC, which seems to contradict the result of a previous study claiming FUCA1 is required for cisplatin-induced cell apoptosis [27], is not utterly surprising."

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"FUCA1 mediates the effect of USP35 on cell proliferation and chemo-resistance in vitro."

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"FUCA1 mediates the impact of USP35 on tumor growth and chemo-resistance in vivo."

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FUCA1 inhibits USP35.

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"Interestingly, FUCA1 ablation almost completely reversed proliferation-promoted effect of USP35 on LoVo and HT29 cells, as indicated by clonogenic and CCK-8 assays (Fig. 5B, C)."

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USP35 affects TNIP2

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USP35 binds TNIP2.

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"USP35 acts as a functional DUB and interacts with ABIN-2."

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"The NF-κB inhibition through USP35-ABIN2 interaction leads to the inhibition of cancer cell proliferation in non-small cell lung carcinoma, cervical cancer, and prostate adenocarcinoma ( xref )."

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"To validate the interaction between USP35 and ABIN-2, HEK293T cells were transiently transfected with Myc tagged USP35 alone or in combination with Flag tagged ABIN-2."

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"To validate the interaction between USP35 and ABIN-2, HEK293T cells were transiently transfected with Myc-tagged USP35 alone or in combination with Flag-tagged ABIN-2."

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"Further, to examine if endogenous USP35 could bind to endogenous ABIN-2, lysates of LNCaP cells were immunoprecipitated with anti-ABIN-2 antibody and probed for USP35 by anti-USP35 antibody."

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"In addition, endogenous USP35 binding to ABIN-2 was also observed in HeLa cells."

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"Further, to examine if endogenous USP35 could bind to endogenous ABIN-2, lysates of LNCaP cells were immunoprecipitated with anti-ABIN-2 antibody and probed for USP35 by anti-USP35 antibody."

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"In addition, endogenous USP35 binding to ABIN-2 was also observed in HeLa cells (Figure xref )."

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USP35 deubiquitinates TNIP2.

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"These data illustrated that USP35 could promote ABIN-2 deubiquitination and decrease its proteasomal degradation."

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"USP35 deubiquitinates and stabilizes ABIN-2 protein."

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"Together, these data illustrated that USP35 could up-regulate the expression of ABIN-2 by promoting ABIN-2 deubiquitination and decreasing its proteasomal degradation."

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"Subsequently, we presented a serial evidence to show that USP35 could deubiquitinate and stabilize ABIN-2 in cancer cells."

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Modified USP35 leads to the deubiquitination of TNIP2. 1 / 1

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"Immunoprecipitation with Flag-ABIN-2 followed by HA-Ub immunoblotting showed overexpression of USP35 dramatically decreased the ABIN-2 ubiquitination."

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USP35 activates TNIP2.

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"The results showed that overexpression of USP35 significantly extended the half-life of ABIN-2, while silenced expression of USP35 shortened the half-life of ABIN-2, indicating that USP35 promotes ABIN-2 protein stabilization."

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"Furthermore, USP35 can increase the activity of ABIN-2 by stabilizing its protein."

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USP35 inhibits TNIP2.

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USP35 inhibits TNIP2. 1 / 2

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"To investigate the mechanism how USP35 inhibits the RIG-I-MAVS pathway, we examined the interaction between USP35 and MAVS."

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"Reciprocal Co-IP assay displayed that endogenous USP35 could bind to endogenous MAVS (Fig. 3D, E)."

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"To validate whether USP35 directly interacts with MAVS, we performed a GST Pull-down assay using the purified USP35 protein and detected a direct interaction between GST-USP35 and MAVS (Fig. 3F)."

40016186

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"To explore whether the binding of USP35 to MAVS is regulated by VSV virus stimulation, we infected cells with the VSV virus."

40016186

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"The interaction between USP35 and MAVS was enhanced in a time-dependent manner following VSV treatment (Fig. 3C)."

40016186

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"To identify the domains involved in the binding of USP35 to MAVS, we constructed a series of truncations of MAVS."

40016186

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"USP35 directly binds to MAVS and removes the K63-linked polyubiquitin chain of MAVS, a process dependent on the enzyme activity of USP35."

40016186

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"USP35 interacts with MAVS in vivo and in vitro."

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"To investigate the mechanism how USP35 inhibits the RIG-I-MAVS pathway, we examined the interaction between USP35 and MAVS."

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USP35 binds MAVS and K63. 1 / 1

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"USP35 directly binds to MAVS and removes the K63-linked polyubiquitin chain of MAVS, a process dependent on the enzyme activity of USP35."

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USP35 affects SNAI1

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"USP35 interacts with Snail1."

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"USP35 interacts with Snail1 to enhance its stability by removing its polyubiquitination chain."

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"We further explored the interaction between USP35 and Snail1 in GC cells using reciprocal IP."

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"As shown in Fig. 2F, deletion of the C-terminal USP domain abrogated the interaction with Snail1, indicating that the USP domain at the C-terminus of USP35 mediated the interaction between USP35 and Snail1."

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"To further examine the association between USP35 and Snail1 at the protein level, we measured the abundance of USP35 and Snail1 in various cancer cell lines, including liver, breast, prostate, and gastric cancers."

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"USP35 interacts with and deubiquitinates Snail1, thereby increasing Snail1 protein levels."

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"Further studies verified that USP35 can interact with Snail1 and that the USP catalytic domain at the C-terminus of USP35 participates in its interaction with Snail1."

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"Mechanistically, USP35 interacted with Snail1 and removed its polyubiquitinated chain, thereby increasing its stability."

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"As shown in Fig. xref F, deletion of the C-terminal USP domain abrogated the interaction with Snail1, indicating that the USP domain at the C-terminus of USP35 mediated the interaction between USP35 and Snail1."

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USP35 increases the amount of SNAI1.

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"USP35 overexpression increased the Snail1 protein levels, whereas USP35 depletion decreased Snail1 protein levels."

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"Our results showed that overexpression of USP35 increased the protein level of Snail1 in these GC cells (Fig. 1C) in a dose-dependent manner (Fig. 1D), but USP35 did not change the mRNA level of Snail1 (Supplementary Fig. S4)."

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"As shown in Fig. 1L, MG132 treatment abrogated USP35 siRNA-induced Snail1 degradation, indicating that USP35 increased Snail1 expression by inhibiting proteasomal degradation."

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"The results revealed that wild-type USP35 (WT-USP35) dramatically increased Snail1 protein levels, whereas USP35-C450A did not affect Snail1 protein levels, indicating that the enzymatic activity of USP35 is necessary for its regulation (Fig. 1G)."

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USP35 bound to SNAI1 increases the amount of SNAI1. 1 / 1

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"USP35 interacts with and deubiquitinates Snail1, thereby increasing Snail1 protein levels."

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USP35 deubiquitinates SNAI1.

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"Altogether, we found that USP35 can deubiquitinate Snail1 and increase its expression, thereby contributing to the malignant progression of GC."

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"USP35 promoted GC cell metastasis by deubiquitinating and stabilizing Snail1."

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"Subsequently, we determined whether USP35 deubiquitinates Snail1."

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"A recent study suggests that USP35 interacts with STING to regulate STING activity and suppresses the antiviral type-I interferon response [ xref ]."

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"Zhang et al. reported that the deubiquitinase USP35 directly interacts with STING ( xref )."

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"Zhang et al. reported that USP35 directly interacts with STING and deubiquitinates STING."

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USP35 inhibits STING1.

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"As mentioned above, USP35 can directly deubiquitinate STING with K6/K11/K27/K29/K63-linked polyubiquitin chains and inhibit STING."

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"Our data further showed that USP35 can directly deubiquitinate and inactivate STING."

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"Knockdown of USP35 increases the activation of the STING signaling pathway [134] ."

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"In ovarian cancer, USP35 can directly deubiquitinate and inactivate the stimulator of interferon genes protein, decreasing the sensitivity of tumor cells to cisplatin ( xref )."

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"Of note, USP35 negatively regulates STING activity in the DNA-sensing pathway [17]."

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"Previous authors have demonstrated that USP35 negatively regulates STING in the DNA signaling pathway, and our current work demonstrates that USP35 also interacts with MAVS in the RNA signaling pathway."

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USP35 deubiquitinates STING1.

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"In ovarian cancer, USP35 deubiquitinates STING and affects STING-mediated interferon signaling 34."

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"For example, USP35 promotes ovarian cancer development by deubiquitinating and inactivating STING [34]."

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"Zhang et al. reported that USP35 directly interacts with STING and deubiquitinates STING."

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"In ovarian cancer, USP35 can directly deubiquitinate and inactivate the stimulator of interferon genes protein, decreasing the sensitivity of tumor cells to cisplatin (16)."

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"Our data further showed that USP35 can directly deubiquitinate and inactivate STING."

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USP35 dephosphorylates STING1.

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USP35 leads to the dephosphorylation of STING1. 1 / 1

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"USP35 knockdown enhances the phosphorylation of STING, TBK1, and IRF3 and reinforces the endogenous interaction between STING and TBK1; it also promotes the expression of type I IFNs."

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USP35 affects ferroptosis

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USP35 inhibits ferroptosis.

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"Knockdown of USP35 can inhibit the progression of lung cancer, promote ferroptosis, and increase the sensitivity of lung cancer cells to cisplatin and paclitaxel chemotherapy [142]."

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"Our study uncovers a novel mechanism by which USP35 inhibits ferroptosis in ER+ breast cancer."

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"Knockdown of USP35 promoted cancer cell ferroptosis and inhibited cancer cell growth and metastasis (50)."

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"Despite this, the knockdown of USP35 resulted in increased Lipid ROS levels and inhibited the growth of TNBC cells MDA-MB-231 and SUM159PT (Supplementary Fig. 5B, 1G, 5C), whereas USP35 overexpression partially inhibited ferroptosis induced by Erastin in MDA-MB-231 cells (Supplementary Fig. 9)."

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"Furthermore, USP35 did not interact with BRD4 in TNBC cells (Supplementary Fig. 5D), suggesting that USP35 inhibited ferroptosis independent of the BRD4-SLC7A11 axis in TNBC although BRD4 and SLC7A11 mRNA levels were positively correlated (Supplementary Fig. 7B), which was different from in ER+ breast cancer (Fig. 4)."

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"In lung cancer cells, USP35 interacts directly with FPN1 to maintain its protein stability and prevent iron overload and ferroptosis (Tang Z. et al., 2021)."

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"USP35 combined with transportin (FPN) synergistically stabilized serum ferritin levels and inhibited ferroptosis to delay lung cancer cell growth (124)."

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"In this study, we uncovered that USP35 inhibited ferroptosis of ER+ breast cancer cells."

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"To understand the mechanism by which USP35 inhibits ferroptosis, we examined whether knockdown of USP35 affected the expressions of key ferroptosis regulators in two ER+ breast cancer cell lines."

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"Similarly, the deubiquitinase USP35 stabilized ferroportin and blocked ferroptosis in lung cancer cells [82]."

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USP35 activates ferroptosis.

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"These results indicate that USP35 silencing enhances ferroptosis and growth inhibition of ER+ breast cancer cells invoked by ferroptotic stimuli."

39820080

➶

reach

"Our results demonstrated that BRD4 inhibition with (+)-JQ-1 treatment significantly inhibited the ER+ breast tumors enhanced by USP35 overexpression, along with decrease of SLC7A11 protein level, and increase of 4-HNE protein levels (Fig. 7), supporting that BRD4 mediated USP35 inhibition of ferroptosis in ER+ breast tumors.Reported studies have shown SLC7A11 expression can be regulated at translational and post-translational levels ."

39820080

➶

reach

"Together, these results support the notion that USP35 promotes the growth of ER+ breast cancer cells by inhibiting ferroptosis."

39820080

➶

reach

"USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis."

39820080

➶

reach

"Additionally, USP35 targeted ferroportin and induced ferroptosis in NSCLC (87)."

36727069

➶

reach

"USP35 promotes the growth of ER+ breast cancer cells by inhibiting ferroptosis."

39820080

USP35 affects BRD4

| 11 6

USP35 binds BRD4.

| 3 6

USP35 binds BRD4. 9 / 9

| 3 6

➶

reach

"Mechanistically, USP35 interacted with, deubiquitinated, and stabilized BRD4."

39820080

➶

reach

"To further examine how USP35 regulates BRD4 protein level, we performed immunoprecipitation analysis to examine whether there is an interaction between USP35 and BRD4."

39820080

➶

reach

"Our study uncovers that USP35 interacts with and deubiquitinates BRD4, and enhances SLC7A11 expression in ER+ breast cancer."

39820080

➶

sparser

"To further examine how USP35 regulates BRD4 protein level, we performed immunoprecipitation analysis to examine whether there is an interaction between USP35 and BRD4."

39820080

➶

sparser

"Immunoprecipitation data showed that Flag-tagged BRD4 interacted with USP35 in transiently transfected 293T17 cells (Fig. xref )."

39820080

➶

sparser

"Together, our results demonstrate that USP35 interacts with BRD4, and regulates BRD4 protein level by increasing BRD4 protein stability through deubiquitination in ER+ breast cancer cells."

39820080

➶

sparser

"Considering that BRD4 interacts with USP35, and regulates SLC7A11 level, we hypothesized that USP35 via BRD4 regulates SLC7A11 level and ferroptosis in ER+ breast cancer cells."

3 | 2 1

BRPF1 binds USP35. 3 / 6

3 | 2 1

➶

sparser

"First of all, the co-immunoprecipitation (co-IP) analysis with an anti-USP35 indicated that USP35 could directly interact with BRPF1, implicating the endogenous interactions (Fig. xref )."

36357379

➶

reach

"USP35 interacts with and deubiquitinates BRPF1 in PRAD cells."

36357379

➶

reach

"Considering that epigenetic deregulation contributes to PRAD progression and BRPF1 is less reported in PRAD, we thus decided to confirm the associations between USP35 and BRPF1."

36357379

USP35 deubiquitinates BRPF1.

| 4

USP35 deubiquitinates BRPF1. 4 / 4

| 4

➶

reach

"USP35 deubiquitinates BRPF1 to activate SREBP2 expressions, thereby strengthening the MVA crosstalk in PRAD progression."

36357379

➶

reach

"In addition, USP35 can accelerate prostate cancer growth by deubiquitinating BRPF1 [37]."

37993419

➶

reach

"Mechanistically, we found that USP35 could directly deubiquitinate and stabilize BRPF1 proteins."

36357379

➶

reach

"USP35 interacts with and deubiquitinates BRPF1 in PRAD cells."

36357379

USP35 increases the amount of BRPF1.

| 2

USP35 increases the amount of BRPF1. 2 / 2

| 2

➶

| 12

USP35 activates HYCC1. 10 / 12

| 12

➶

reach

"Moreover, USP35 knockdown impaired the migration and invasion capabilities of HCC cells (Fig. 3L–O)."

37993419

➶

reach

"USP35 deficiency suppresses HCC development in vivo."

37993419

➶

reach

"Together, these data suggest that USP35 promotes HCC development in vivo."

37993419

➶

reach

"Our data also demonstrate that USP35 promotes HCC development by stabilizing ABHD17C and activates the PI3K/AKT pathway.The oncogenic function of USP35 in other cancers has been well characterized."

37993419

➶

reach

"We also observed that USP35 knockdown repressed the development of xenograft HCC tumors in vivo."

37993419

➶

reach

"In summary, these results suggest that USP35 may promote HCC development by stabilizing ABHD17C, thereby facilitating tumor progress through the activation of the PI3K/AKT signal cascade."

37993419

➶

reach

"Given the diversity of its substrates, it will be important to investigate whether USP35 promotes HCC development by additional targets other than ABHD17C.ABHD17 depalmitoylases can regulate palmitoylation of N-RAS to change its subcellular localization, and selective inhibitor of ABHD17 proteins is reported to repress N-RAS signaling and impair acute myeloid leukemia cell growth [15, 16]."

37993419

➶

reach

"In line with these reports, we found that the PI3K/AKT pathway is disrupted in USP53-deficient HCC cells, which is likely caused by a lack of sufficient ABHD17C.In conclusion, our study provides evidence that USP35 promotes HCC development by stabilizing ABHD17C (Fig. 8)."

37993419

➶

reach

"USP35 promotes HCC development by stabilizing ABHD17C and activating the PI3K/AKT signaling pathway."

37993419

➶

reach

"In support of these in vitro observations, xenograft assay data also showed that USP35 deficiency repressed HCC development in vivo, characterized by reduced proliferation and disrupted PI3K/AKT signaling."

37993419

USP35 inhibits HYCC1.

| 2

USP35 inhibits HYCC1. 2 / 2

| 2

➶

reach

"Furthermore, overexpression of ABHD17C could rescue the defects in HCC cells caused by USP35 deficiency."

37993419

➶

reach

"Knockdown of USP35 causes reduced proliferation, cell cycle arrest, increased apoptosis, and mitigated migration and invasion of HCC cells."

37993419

USP35 affects FUNDC1

| 9 5

USP35 binds FUNDC1.

| 3 5

USP35 binds FUNDC1. 8 / 8

| 3 5

➶

reach

"Mechanistically, USP35 interacted with and stabilized FUNDC1, a positive regulator of mitochondrial metabolism."

39406943

➶

reach

"USP35 interacted with and stabilized FUNDC1 by repressing its ubiquitination."

39406943

➶

reach

"The data from these assays indicated a direct interaction between USP35 and FUNDC1 within the cells (Fig. 4D)."

39406943

➶

sparser

"Mechanistically, it was discovered that USP35 interacted with FUNDC1 and executed deubiquitination processes, thereby enhancing the stability of FUNDC1."

39406943

➶

sparser

"The data from these assays indicated a direct interaction between USP35 and FUNDC1 within the cells (Fig. xref )."

39406943

➶

sparser

"This highlights the critical role of the USP35-FUNDC1 axis in enhancing the neuroprotective function of both hUC-MSCs and their secreted EVs (Fig. xref )."

2 | 7

USP35 is phosphorylated. 5 / 5

| 5

➶

sparser

"In addition, AKT, a key effector of PI3K, phosphorylated USP35 at Serine613, which promoted USP35 nuclear translocation, ERα transcriptional activity, and the growth of ER+ breast cancer cells."

34131114

➶

sparser

"Using antibodies recognizing the phosphorylated AKT consensus peptides, we found that there was robust phosphorylation of USP35 WT , whereas phosphorylation of USP35 S613A was greatly diminished in T-47D cells (Fig. xref )."

34131114

➶

sparser

"The result showed that USP35 WT was robustly phosphorylated, whereas USP35 S613A phosphorylation was lost in the presence of activated AKT (Fig. xref )."

34131114

➶

sparser

"Similarly, USP35 S613A phosphorylation was reduced compared with USP35 WT in MCF-7 cells."

34131114

➶

sparser

"Importantly, AKT inhibitor MK2206 inhibited USP35 WT phosphorylation in MCF-7 cells (Fig. xref )."

34131114

USP35 is phosphorylated on S613. 2 / 4

2 | 2

➶

sparser

"AKT promotes nuclear translocation of USP35 and enhances ERα transcriptional activity by phosphorylating USP35 at Ser613."

34131114

➶

sparser

"These data indicate that AKT interacts with USP35 and phosphorylates USP35 at Ser613."

34131114

USP35 is ubiquitinated.

| 3

USP35 is ubiquitinated. 3 / 3

| 3

➶

sparser

"Compared to vector control, USP35 WT decreased ubiquitination of ERα (Fig. xref ), whereas USP35 C450A did not affect ubiquitination of ERα."

34131114

➶

sparser

"In addition, result from HA-ubiquitin immunoprecipitation followed by immunoblotting with the anti-ERα antibodies also showed that USP35 WT significantly reduced ubiquitination of ERα (Fig. xref )."

| 3 6

USP35 binds BRD4. 9 / 9

| 3 6

➶

reach

"Mechanistically, USP35 interacted with, deubiquitinated, and stabilized BRD4."

39820080

➶

reach

"To further examine how USP35 regulates BRD4 protein level, we performed immunoprecipitation analysis to examine whether there is an interaction between USP35 and BRD4."

39820080

➶

reach

"Our study uncovers that USP35 interacts with and deubiquitinates BRD4, and enhances SLC7A11 expression in ER+ breast cancer."

39820080

➶

sparser

"To further examine how USP35 regulates BRD4 protein level, we performed immunoprecipitation analysis to examine whether there is an interaction between USP35 and BRD4."

39820080

➶

sparser

"Immunoprecipitation data showed that Flag-tagged BRD4 interacted with USP35 in transiently transfected 293T17 cells (Fig. xref )."

39820080

➶

sparser

"Together, our results demonstrate that USP35 interacts with BRD4, and regulates BRD4 protein level by increasing BRD4 protein stability through deubiquitination in ER+ breast cancer cells."

39820080

➶

sparser

"Considering that BRD4 interacts with USP35, and regulates SLC7A11 level, we hypothesized that USP35 via BRD4 regulates SLC7A11 level and ferroptosis in ER+ breast cancer cells."

39820080

➶

sparser

39820080

➶

sparser

39820080

BRD4 activates USP35.

| 3

BRD4 activates USP35. 3 / 3

| 3

➶

reach

"Since BRD4 mediates the effects of USP35 on inhibiting ferroptosis in ER+ breast cancer cells (Fig. 6), we tested the effect of BRD4 inhibition on USP35-enhanced growth of ER+ breast cancer cells in vivo."

39820080

➶

reach

"Consequentially, BRD4 mediated USP35-induced SLC7A11 upregulation, inhibiting ferroptosis and promoting the growth of ER+ breast cancer cells."

39820080

➶

reach

"These data support that BRD4 mediates the effects of USP35 in promoting tumor growth and inhibiting ferroptosis in ER+ breast tumors."

39820080

BRD4 inhibits USP35.

| 1

BRD4 inhibits USP35. 1 / 1

| 1

➶

reach

39820080

USP35 affects apoptotic process

| 12

USP35 inhibits apoptotic process.

| 9

USP35 inhibits apoptotic process. 9 / 9

| 9

➶

reach

39406943

➶

reach

"Collectively, these findings suggest that excessive USP35 enhances the capacity of hUC-MSCs and hUC-MSC-EVs to reduce apoptosis and ROS stress in cocultured SH-SY5Y OGD/R cells."

39406943

➶

reach

"Further functional studies showed that knockdown USP35 expression inhibited cell proliferation and promoted apoptosis."

39714773

➶

reach

"USP35 resists cell apoptosis by stabilizing anti-apoptotic factor BIRC3 and relieves endoplasmic reticulum stress (ERS) by deubiquitinating RRBP1 [20, 22]."

36864055

➶

reach

"Knockdown of USP35 causes reduced proliferation, cell cycle arrest, increased apoptosis, and mitigated migration and invasion of HCC cells."

37993419

➶

reach

"Additionally, USP35 knockdown led to an increased number of cells arrested in the G /G phase (Fig. 3H, I), as well as enhanced apoptosis in HCC cells (Fig. 3J, K)."

37993419

➶

reach

"Strikingly, USP35 overexpression markedly reduced cytotoxic agents-induced cell apoptosis (Fig. 2F, G), while USP35 knockdown led to increased drug-induced cell apoptosis (Fig. S3C, D)."

36864055

➶

reach

"It is possible that USP35 inhibition may synergize with Taxol to induce apoptosis or cell arrest, based on the result that USP35 deficiency itself already leads to multiple mitotic errors, and this outcome could be further exacerbated by Taxol treatment [34]."

36864055

➶

reach

"The results from flow cytometry assays demonstrated that decreased USP35 expression elevated the apoptosis rate of Huh-7 (1.5 vs. 10.1%; Fig. 3E) and Hep3B (1.1 vs. 6.2%; Fig. 3F) cells."

37594129

USP35 activates apoptotic process.

| 3

USP35 activates apoptotic process. 3 / 3

| 3

➶

reach

"We then investigated whether USP35 overexpression could potentiate the function of hUC-MSC and hUC-MSC-EV in alleviating apoptosis and reducing ROS stress in SH-SY5Y OGD/R cells."

39406943

➶

reach

"Strikingly, USP35 overexpression markedly reduced cytotoxic agents-induced cell apoptosis (Fig. 2F, G), while USP35 knockdown led to increased drug-induced cell apoptosis (Fig. S3C, D)."

36864055

➶

reach

"USP35 iso2 led to ER stress, BAP31 cleavage and activation of caspase-8 and caspase-3, resulting in apoptosis [XREF_BIBR]."

31208841

USP35 affects Neoplasms

| 10

USP35 activates Neoplasms.

| 9

USP35 activates Neoplasms. 9 / 9

| 9

➶

reach

"Consistent with our previous finding , USP35 overexpression promoted the growth of ER+ breast tumors, whereas (+)-JQ-1 inhibited the tumor growth increased by USP35 overexpression (Fig. 7B, D, E)."

39820080

➶

reach

"USP35 is overexpressed in KIRC and associated with poor prognosis, likely promoting tumor progression through oncogenic pathways and immune modulation."

40188027

➶

reach

"We observed that USP35 overexpression markedly promoted tumor growth and drug resistance, but depleting FUCA1 in USP35-overexpressed cells reversed the tumor growth to the basal levels, and re-sensitized the tumors to the chemo-treatments, as indicated by representative images, tumor weight and growth curve (Fig. 6A–C)."

36864055

➶

reach

"We also observed that USP35 knockdown repressed the development of xenograft HCC tumors in vivo."

37993419

➶

reach

"In summary, these results suggest that USP35 may promote HCC development by stabilizing ABHD17C, thereby facilitating tumor progress through the activation of the PI3K/AKT signal cascade."

37993419

➶

reach

"In this study, we highlighted the SREBP2-dependent MVA crosstalk is activated by USP35/BRFP1 axis to drive tumor progression."

36357379

➶

reach

"Importantly, depletion of USP35 significantly enhances the anti-tumor immunity and synergizes with oncolytic virotherapy to suppress xenograft tumor growth of melanoma cells."

40016186

➶

reach

"Depletion of USP35 promotes ferroptosis and suppresses lung cancer cell growth and tumor progression [16]."

40016186

➶

reach

"Through a systematic survey in the association of human ubiquitin-specific proteases with patient prognosis of renal clear cell carcinoma and subsequent phenotypic validation, we uncovered the tumor-promoting role of USP35."

37173391

USP35 inhibits Neoplasms.

| 1

USP35 inhibits Neoplasms. 1 / 3

| 1

➶

reach

"Targeting USP35 could potentially inhibit tumor progression and overcome resistance to therapy."

40188027

USP35 affects BIRC5

2 | 7 3

USP35 binds BIRC5.

2 | 2 3

BIRC5 binds USP35. 5 / 7

2 | 2 3

➶

reach

"USP35/USP38 interacted with and deubiquitinated survivin."

34438346

➶

sparser

"To investigate the mechanism by which USP35 regulates the protein stability of survivin, we next tested whether USP35 interacts with survivin."

34438346

➶

3 | 4 4

➶

reach

"USP35 acts as a functional DUB and interacts with ABIN-2."

26348204

➶

sparser

"The NF-κB inhibition through USP35-ABIN2 interaction leads to the inhibition of cancer cell proliferation in non-small cell lung carcinoma, cervical cancer, and prostate adenocarcinoma ( xref )."

39507445

➶

reach

"To validate the interaction between USP35 and ABIN-2, HEK293T cells were transiently transfected with Myc tagged USP35 alone or in combination with Flag tagged ABIN-2."

26348204

➶

sparser

"To validate the interaction between USP35 and ABIN-2, HEK293T cells were transiently transfected with Myc-tagged USP35 alone or in combination with Flag-tagged ABIN-2."

26348204

➶

reach

"Further, to examine if endogenous USP35 could bind to endogenous ABIN-2, lysates of LNCaP cells were immunoprecipitated with anti-ABIN-2 antibody and probed for USP35 by anti-USP35 antibody."

26348204

➶

reach

"In addition, endogenous USP35 binding to ABIN-2 was also observed in HeLa cells."

26348204

➶

sparser

"Further, to examine if endogenous USP35 could bind to endogenous ABIN-2, lysates of LNCaP cells were immunoprecipitated with anti-ABIN-2 antibody and probed for USP35 by anti-USP35 antibody."

26348204

➶

sparser

"In addition, endogenous USP35 binding to ABIN-2 was also observed in HeLa cells (Figure xref )."

26348204

USP35 affects CDH1

| 7 4

USP35 binds CDH1.

| 2 4

USP35 binds CDH1. 6 / 6

| 2 4

➶

reach

"Interestingly, we also observed that USP35 could bind to CDH1."

29449677

➶

sparser

"USP35 can bind to CDH1 and restore Aurora B levels that have been reduced by CDH1-induced ubiquitination, suggesting that USP35 counteracts the APC CDH1 -mediated ubiquitination of Aurora B. This possibility supports the occurrence of mitotic defects in USP35-depleted cells, as dysregulated levels of Aurora B protein may interfere with the progression of mitosis."

29449677

➶

reach

"USP35 can bind to CDH1 and restore Aurora B levels that have been reduced by CDH1 induced ubiquitination, suggesting that USP35 counteracts the APC CDH1 -mediated ubiquitination of Aurora B."

29449677

➶

sparser

"We surmise that Aurora B forms a complex with USP35 and CDH1 during mitosis, whereas USP35 mostly maintains Aurora B levels because the CDK1-dependent ubiquitination of CDH1 inhibits interaction with APC/C in the early phase."

29449677

➶

sparser

"Interestingly, USP35 transcript levels were found to be controlled by the FoxM1 transcription factor, and interestingly Cdh1 also interacts with USP35 even though it was shown to not affect its stability."

32201366

➶

sparser

"Interestingly, we also observed that USP35 could bind to CDH1 (Fig. xref )."

29449677

USP35 decreases the amount of CDH1.

| 3

USP35 decreases the amount of CDH1. 3 / 3

| 3

➶

reach

"Silencing USP35 significantly reduced N-cadherin levels and increased E-cadherin expression (p < 0.01), indicating its role in regulating EMT in KIRC cells (F ig."

40188027

➶

reach

"Furthermore, we investigated the regulation of USP35 on EMT markers and found that USP35 overexpression decreased the protein levels of the epithelial marker E-cadherin and increased those of the mesenchymal markers N-cadherin and Vimentin in GC cells (Fig. 1F)."

| 3

ESR1 binds USP35. 3 / 3

| 3

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sparser

"Results from immunoprecipitation experiment in MCF-7 cells revealed that USP35 and ERα can be reciprocally coimmunoprecipitated (Figs. xref f, xref ), indicating that USP35 interacted with endogenous ERα."

34131114

➶

sparser

"Using different deletion mutant of USP35, we found that USP35 interacts with ERα via its USP35 domain (data not shown)."

34131114

➶

sparser

"The activated USP35 interacts with ERα, boosting its transcriptional activity, which diminishes the effectiveness of tamoxifen and fulvestrant treatments [ xref ]."

38702734

USP35 activates ESR1.

| 3

USP35 activates ESR1. 3 / 3

| 3

➶

reach

"Similar effects have been observed in breast cancer, where USP35 enhances tumorigenesis by stabilizing estrogen receptor α (ERα), leading to increased proliferation and metastasis [37]."

40188027

➶

reach

"For example, USP35 promotes tumorigenesis in estrogen receptor (ER)-positive breast cancer by stabilizing and activating estrogen receptor α (Erα) to increases Erα transcriptional activity [19]."

36864055

➶

reach

"USP35, regulated by estrogen and AKT, promotes breast tumorigenesis by stabilizing and enhancing transcriptional activity of estrogen receptor alpha."

34131114

USP35 ubiquitinates ESR1.

| 2

USP35 ubiquitinates ESR1. 2 / 2

| 2

➶

sparser

"Compared to vector control, USP35 WT decreased ubiquitination of ERα (Fig. xref ), whereas USP35 C450A did not affect ubiquitination of ERα."

34131114

➶

sparser

34131114

USP35 deubiquitinates ESR1.

1 | 1

USP35 leads to the deubiquitination of ESR1. 1 / 2

1 | 1

➶

reach

"Mechanistically, USP35 enhanced ERalpha stability by interacting and deubiquitinating ERalpha, and transcriptional activity of ERalpha by interacting with ERalpha in DNA regions containing estrogen response element."

34131114

SNAI1 affects USP35

| 5 5

SNAI1 binds USP35.

| 4 5

USP35 binds SNAI1. 9 / 9

| 4 5

➶

sparser

"USP35 interacts with Snail1."

38250150

➶

sparser

"USP35 interacts with Snail1 to enhance its stability by removing its polyubiquitination chain."

39605891

➶

reach

"We further explored the interaction between USP35 and Snail1 in GC cells using reciprocal IP."

38250150

➶

reach

38250150

➶

reach

38250150

➶

reach

"USP35 interacts with and deubiquitinates Snail1, thereby increasing Snail1 protein levels."

38250150

➶

sparser

"Further studies verified that USP35 can interact with Snail1 and that the USP catalytic domain at the C-terminus of USP35 participates in its interaction with Snail1."

38250150

➶

sparser

"Mechanistically, USP35 interacted with Snail1 and removed its polyubiquitinated chain, thereby increasing its stability."

38250150

➶

sparser

38250150

SNAI1 activates USP35.

| 1

SNAI1 activates USP35. 1 / 1

| 1

➶

reach

"Snail1 depletion partially abrogated the biological effects of USP35."

38250150

FUNDC1 affects USP35

| 5 5

FUNDC1 binds USP35.

| 3 5

USP35 binds FUNDC1. 8 / 8

| 3 5

➶

reach

"Mechanistically, USP35 interacted with and stabilized FUNDC1, a positive regulator of mitochondrial metabolism."

39406943

➶

reach

"USP35 interacted with and stabilized FUNDC1 by repressing its ubiquitination."

39406943

➶

reach

"The data from these assays indicated a direct interaction between USP35 and FUNDC1 within the cells (Fig. 4D)."

39406943

➶

sparser

"Mechanistically, it was discovered that USP35 interacted with FUNDC1 and executed deubiquitination processes, thereby enhancing the stability of FUNDC1."

39406943

➶

sparser

"The data from these assays indicated a direct interaction between USP35 and FUNDC1 within the cells (Fig. xref )."

39406943

➶

sparser

"This highlights the critical role of the USP35-FUNDC1 axis in enhancing the neuroprotective function of both hUC-MSCs and their secreted EVs (Fig. xref )."

39406943

➶

sparser

"However, the specific domain of FUNDC1 that interacts with USP35 has yet to be identified."

39406943

➶

sparser

39406943

FUNDC1 activates USP35.

| 2

FUNDC1 activates USP35. 2 / 2

| 2

➶

reach

"Knockdown of FUNDC1 abolished the effects of excessive USP35 in strengthening the protective roles of hUC-MSC and hUC-MSC-EV on SH-SY5Y OGD/R."

39406943

➶

reach

39406943

USP35 affects Stomach Neoplasms

| 9

USP35 activates Stomach Neoplasms. 9 / 9

| 9

➶

reach

"We performed rescue experiments to determine whether USP35 promotes GC cell invasion and migration via Snail1."

38250150

➶

reach

"6 B-E, Snail1 knockdown abolished USP35 overexpression-induced GC cell invasion and migration."

38250150

➶

reach

"USP35 promotes GC invasion and migration, at least partially by regulating Snail1."

38250150

➶

reach

"Transwell and scratch wound healing assays suggested that USP35 knockdown inhibited the invasion and migration of GC cells (Figs."

38250150

➶

reach

"We also verified that USP35 promotes the proliferation and survival of GC cells, which is consistent with certain findings reported previously 30."

38250150

➶

reach

"Furthermore, USP35 promoted the invasion and migration of GC cells depending on its DUB activity."

38250150

➶

reach

"USP35 promotes GC metastasis in vivo."

38250150

➶

reach

"These results suggest that USP35 relies on DUB activity to promote GC metastasis in vivo."

38250150

➶

reach

"We found that overexpression of wild-type USP35 promoted GC cell invasion and migration in vitro and facilitated tumorigenesis and metastasis in vivo."

38250150

USP35 affects SLC7A11

| 9

USP35 increases the amount of SLC7A11.

| 6

USP35 increases the amount of SLC7A11. 5 / 5

| 5

➶

reach

"USP35 knockdown reduced the protein level of cystine/glutamate transporter SLC7A11 (Fig. 3A)."

39820080

➶

reach

"Conversely, overexpression of USP35 also increased the SLC7A11 protein level (Fig. 3B), indicating that USP35 is important for SLC7A11 expression in ER+ breast cancer cells."

39820080

➶

reach

"However, MG132 (a proteasome inhibitor) treatment could not rescue the SLC7A11 protein level that was inhibited by USP35 knockdown (Supplementary Fig. 4), indicating that USP35 did not upregulate SLC7A11 through deubiquitination."

39820080

➶

reach

"Conversely, although USP35 overexpression increased SLC7A11 protein level compared with vector control, BRD4 inhibitor (+)-JQ-1 treatment reduced the increase in SLC7A11 protein level induced by USP35 overexpression (Fig. 6D)."

39820080

➶

reach

"Furthermore, immunohistochemistry analysis revealed that USP35 increased the levels of SLC7A11, whereas (+)-JQ-1 treatment significantly reduced the levels of SLC7A11, and increased the level of 4-HNE, a marker of ferroptosis, in ER+ breast tumors (Fig. 7F, G)."

39820080

USP35 bound to BRD4 increases the amount of SLC7A11. 1 / 1

| 1

➶

reach

"Our study uncovers that USP35 interacts with and deubiquitinates BRD4, and enhances SLC7A11 expression in ER+ breast cancer."

39820080

USP35 decreases the amount of SLC7A11.

| 2

USP35 decreases the amount of SLC7A11. 2 / 2

| 2

➶

reach

39820080

➶

reach

"Consequently, we found that BRD4 overexpression rescued the decrease in SLC7A11 protein level induced by USP35 knockdown (Fig. 6A)."

39820080

USP35 activates SLC7A11.

| 1

USP35 activates SLC7A11. 1 / 1

| 1

➶

reach

"Consequentially, BRD4 mediated USP35-induced SLC7A11 upregulation, inhibiting ferroptosis and promoting the growth of ER+ breast cancer cells."

39820080

USP35 affects PKM2

| 7 2

USP35 binds PKM2.

| 2 2

USP35 binds PKM2. 4 / 4

| 2 2

➶

sparser

"Notably, the Co-IP assay results indicated the existence of an interaction between endogenous USP35 and PKM2 ( xref )."

37594129

➶

reach

"Notably, the Co-IP assay results indicated the existence of an interaction between endogenous USP35 and PKM2 (Fig. 6C and D)."

37594129

➶

sparser

"USP35 binds to PKM2 and regulates PKM2 expression through ubiquitination in HCC."

37594129

➶

reach

"USP35 binds to PKM2 and regulates PKM2 expression through ubiquitination in HCC."

37594129

USP35 activates PKM2.

| 2

USP35 activates PKM2. 2 / 2

| 2

➶

reach

"Furthermore, rescue experiments were performed to investigate whether PKM2 in HCC was mediated by USP35."

| 8

➶

reach

"We found that overexpression of wild-type USP35 promoted GC cell invasion and migration in vitro and facilitated tumorigenesis and metastasis in vivo."

38250150

➶

reach

"We performed rescue experiments to determine whether USP35 promotes GC cell invasion and migration via Snail1."

38250150

➶

reach

"6 B-E, Snail1 knockdown abolished USP35 overexpression-induced GC cell invasion and migration."

38250150

➶

reach

"Furthermore, USP35 promoted the invasion and migration of GC cells depending on its DUB activity."

38250150

➶

reach

"USP35 promotes GC invasion and migration, at least partially by regulating Snail1."

38250150

➶

reach

"Transwell and scratch wound healing assays suggested that USP35 knockdown inhibited the invasion and migration of GC cells (Figs."

38250150

➶

reach

"Knockdown of USP35 causes reduced proliferation, cell cycle arrest, increased apoptosis, and mitigated migration and invasion of HCC cells."

37993419

➶

reach

"Moreover, USP35 knockdown impaired the migration and invasion capabilities of HCC cells (Fig. 3L–O)."

37993419

USP35 activates Neoplasm Invasiveness. 1 / 1

| 1

➶

reach

"Notably, USP35 knockdown sensitized tumors to cisplatin, and cisplatin treatment was reported to enhance CTL infiltration in vivo via cGAS/STING signaling [100, 103]."

38715050

USP35 affects NFE2L2

| 1 8

USP35 binds NFE2L2.

| 8

USP35 binds NFE2L2. 8 / 8

| 8

➶

sparser

"USP35 interacts with NRF2 and facilitates its deubiquitination."

39156988

➶

sparser

"In conclusion, our results suggest that USP35 interacts with NRF2 and deubiquitinates it, thereby regulating its protein stability."

39156988

➶

sparser

"These findings suggest that the USP35-NRF2 axis is a key player in the regulation of therapeutic strategies for esophageal cancer."

39156988

➶

sparser

"In our research, we found that USP35 interacts with NRF2 and aids in its deubiquitination, leading to the inhibition of its proteasomal degradation."

39156988

➶

sparser

"USP35 interacts with NRF2 and promotes NRF2 deubiquitination."

39156988

➶

sparser

"Subsequently, an investigation was conducted to determine the potential interaction between USP35 and NRF2 in order to elucidate the mechanism by which USP35 regulates the protein stability of NRF2."

39156988

➶

sparser

"The results presented in xref demonstrate a mutual interaction between USP35 and NRF2."

39156988

➶

sparser

"Further analysis was carried out to ascertain the specific protein domains through which USP35 and NRF2 interact."

39156988

USP35 activates NFE2L2.

| 1

USP35 activates NFE2L2. 1 / 1

| 1

➶

reach

"Mechanistically, USP35 modulates NRF2 stability through enzymatic deubiquitination."

39156988

USP35 affects ABHD17C

| 9

USP35 activates ABHD17C.

| 5

USP35 activates ABHD17C. 5 / 5

| 5

➶

reach

"In support of this, we found that USP35 deficiency significantly accelerated ABHD17C degradation in HCC cells (Fig. 4E, F)."

37993419

➶

reach

"Our data also demonstrate that USP35 promotes HCC development by stabilizing ABHD17C and activates the PI3K/AKT pathway.The oncogenic function of USP35 in other cancers has been well characterized."

37993419

➶

reach

"In summary, these results suggest that USP35 may promote HCC development by stabilizing ABHD17C, thereby facilitating tumor progress through the activation of the PI3K/AKT signal cascade."

37993419

➶

reach

"USP35 promotes HCC development by stabilizing ABHD17C and activating the PI3K/AKT signaling pathway."

37993419

➶

reach

37993419

USP35 binds ABHD17C.

| 3

USP35 binds ABHD17C. 3 / 3

| 3

➶

reach

"USP35 can interact with and stabilize ABHD17C by inhibiting its ubiquitination."

37993419

➶

reach

"Collectively, these findings demonstrated that USP35 interacted with and stabilized ABHD17C by regulating its ubiquitination in HCC cells."

37993419

➶

reach

"USP35 interacts with and stabilizes ABHD17C in HCC cells."

37993419

USP35 deubiquitinates ABHD17C.

| 1 7

USP35 binds MYC.

| 7

MYC binds USP35. 7 / 7

| 7

➶

sparser

"Co-immunoprecipitation (Co-IP) experiments in 293 T co-transfected with Myc-USP35 and Flag-tagged RIG-I, MAVS, or TBK1 showed that USP35 strongly interacted with MAVS (Fig. xref )."

40016186

➶

sparser

36357379

➶

sparser

"We transfected Flag-Snail1 and HA-Ub, together with Myc-USP35 or empty vector, into HEK293T and MKN-45 cells and performed a Co-IP assay."

38250150

➶

sparser

"We further transfected Myc-USP35 (WT) or the USP35-C450A mutant (CA) with loss of DUB activity, together with HA-Ub and Flag-Snail1, into AGS and HEK293T cells to determine whether the DUB activity of USP35 is indispensable for the deubiquitination of Snail1."

38250150

➶

sparser

"We co-expressed MAVS-Flag, USP35-Myc, and HA-Ub or HA-Ub K63O (K63 only) in 293 T. The results showed that USP35 removed the K63-type ubiquitination of MAVS (Fig. xref )."

40016186

➶

sparser

"Therefore, to investigate the mode of deubiquitination of Snail1 by USP35, we co-transfected Flag-Snail1 with WT HA-Ub, K0 HA-Ub (with all lysine residues in Ub were mutated to arginine), or one among HA-Ub K6, K11, K27, K29, K33, K48, and K63 (in which all lysine residues except those at positions 6, 11, 27, 29, 33, 48, and 63, respectively, were replaced with arginine), together with empty vector or Myc-USP35, into HEK293T cells."

38250150

➶

sparser

"Restoration of Myc-USP35 in USP35-depleted A375 inhibited TBK1 and IRF3 activation upon RNA virus stimulation (Supplementary Fig. xref )."

40016186

USP35 increases the amount of MYC.

| 1

USP35 increases the amount of MYC. 1 / 1

| 1

➶

reach

"USP35 deficiency attenuated the activation of the JAK1/STAT1 pathway and reduced the expression of β-catenin and c-Myc in JeKo-1 cells."

39591978

USP35 affects Carcinogenesis

| 8

USP35 activates Carcinogenesis. 8 / 8

| 8

➶

reach

"USP35 enhances tumorigenesis and stemness potentiality of PRAD cells."

36357379

➶

reach

"In accordance to our speculations, USP35 overexpression could result in the formation of larger prostate tumors relative to those in control mice, suggesting that USP35 significantly promoted tumorigenesis (Fig. 2I)."

36357379

➶

reach

"For example, USP35 promotes tumorigenesis in estrogen receptor (ER)-positive breast cancer by stabilizing and activating estrogen receptor α (Erα) to increases Erα transcriptional activity [19]."

36864055

➶

reach

"We previously showed that deubiquitinase USP35 and ERalpha act in a positive feedback loop to promote the carcinogenesis of ER+ breast cancer although it is unclear whether USP35 regulates cell death in ER+ breast cancer."

39820080

➶

reach

"Furthermore, BRD4 inhibitor (+)-JQ-1 inhibited USP35-enhanced tumorigenesis in vivo."

39820080

➶

reach

"Similar effects have been observed in breast cancer, where USP35 enhances tumorigenesis by stabilizing estrogen receptor α (ERα), leading to increased proliferation and metastasis [37]."

40188027

➶

reach

"Also, USP35 silencing could reduce NSCLC tumorigenesis by downregulating VEGFA."

38953570

➶

reach

"USP35 promotes tumorigenesis of ER+ breast cancer via stabilizing and enhancing the transcriptional activity of ERα ."

39820080

PKM2 affects USP35

| 6 2

PKM2 binds USP35.

| 2 2

USP35 binds PKM2. 4 / 4

| 2 2

➶

sparser

"Notably, the Co-IP assay results indicated the existence of an interaction between endogenous USP35 and PKM2 ( xref )."

37594129

➶

reach

"Notably, the Co-IP assay results indicated the existence of an interaction between endogenous USP35 and PKM2 (Fig. 6C and D)."

37594129

➶

sparser

"USP35 binds to PKM2 and regulates PKM2 expression through ubiquitination in HCC."

37594129

➶

reach

"USP35 binds to PKM2 and regulates PKM2 expression through ubiquitination in HCC."

37594129

PKM2 inhibits USP35.

| 3

PKM2 inhibits USP35. 3 / 3

| 3

➶

reach

"EdU assays demonstrated that PKM2 overexpression significantly abolished the inhibitory effects of USP35 knockdown on proliferation (Fig. 7C and D)."

37594129

➶

reach

"Moreover, increased PKM2 expression significantly decreased the inhibitory effect of USP35 knockdown on migration and invasion in Huh-7-De-USP35 and Hep3B-De-USP35 cells (Fig. 7E-H)."

37594129

➶

reach

"It was found that increased PKM2 expression significantly abolished the inhibitory effects of USP35 knockdown on glucose uptake in Huh-7-De-USP35 and Hep3B-De-USP35 cells (Fig. 8A and E)."

37594129

PKM2 activates USP35.

| 1

PKM2 activates USP35. 1 / 1

| 1

➶

reach

"In addition, PKM2 overexpression significantly rescued the inhibitory effects of USP35 knockdown on tumor growth in vivo (Fig. 7I and J)."

37594129

NFE2L2 affects USP35

| 8

USP35 binds NFE2L2. 8 / 8

| 8

➶

sparser

"USP35 interacts with NRF2 and facilitates its deubiquitination."

39156988

➶

sparser

"In conclusion, our results suggest that USP35 interacts with NRF2 and deubiquitinates it, thereby regulating its protein stability."

39156988

➶

sparser

"These findings suggest that the USP35-NRF2 axis is a key player in the regulation of therapeutic strategies for esophageal cancer."

39156988

➶

sparser

"In our research, we found that USP35 interacts with NRF2 and aids in its deubiquitination, leading to the inhibition of its proteasomal degradation."

39156988

➶

sparser

"USP35 interacts with NRF2 and promotes NRF2 deubiquitination."

39156988

➶

sparser

39156988

➶

sparser

"The results presented in xref demonstrate a mutual interaction between USP35 and NRF2."

39156988

➶

sparser

"Further analysis was carried out to ascertain the specific protein domains through which USP35 and NRF2 interact."

39156988

AKT affects USP35

| 2 6

AKT phosphorylates USP35.

| 2 5

AKT phosphorylates USP35 on S613. 5 / 5

| 1 4

➶

reach

"Furthermore, as a crucial component of the PI3K pathway, AKT phosphorylates USP35 at Ser613."

38702734

➶

sparser

"Furthermore, as a crucial component of the PI3K pathway, AKT phosphorylates USP35 at Ser613."

38702734

➶

sparser

"Furthermore, phosphorylation of Ser613 in USP35 by AKT, an effector of PI3K, is critical for USP35 nuclear translocation and promoting ERα transcriptional activity and the growth of ER+ breast cancer cells."

34131114

➶

sparser

"Collectively, our data indicate that USP35-S613 phosphorylation by AKT is required, but not sufficient, for USP35 enhancement of ERα target gene expression."

34131114

➶

sparser

"In addition, Akt phosphorylating Ser613 in USP35 is critical for USP35 nuclear translocation and enhancing ERα transcriptional activity (Fig. xref )."

34131114

AKT phosphorylates USP35. 2 / 2

| 1 1

➶

sparser

"AKT phosphorylation of USP35 is critical for USP35′s action in ER+ breast cancer cells."

34131114

➶

reach

"In addition, AKT, a key effector of PI3K, phosphorylated USP35 at Serine613, which promoted USP35 nuclear translocation, ERalpha transcriptional activity, and the growth of ER+ breast cancer cells."

34131114

AKT binds USP35.

| 1

AKT binds USP35. 1 / 1

| 1

➶

sparser

"These data indicate that AKT interacts with USP35 and phosphorylates USP35 at Ser613."

34131114

USP35 affects immune response

| 7

USP35 inhibits immune response.

| 6

USP35 inhibits immune response. 6 / 6

| 6

➶

reach

"Knockdown of USP35 enhances the anti-tumor immunity of malignant melanoma to oncolytic virotherapy."

40016186

➶

reach

"Importantly, depletion of USP35 significantly enhances the anti-tumor immunity and synergizes with oncolytic virotherapy to suppress xenograft tumor growth of melanoma cells."

40016186

➶

reach

"Both DNA or RNA induction pathways stimulate the expression of type I interferons, and USP35 knockdown enhances anti-tumor immunity in response to the oncolytic virus therapy."

40016186

➶

reach

"Lastly, USP35 suppressed anti-tumor immunity of type I interferon through the STING/TBK1/IRF3 pathway and as a result, chemoresistance was induced [113,159,160,161]."

37107644

➶

reach

"The knockdown of USP35 enhances the anti-tumor immunity of oncolytic viruses in malignant melanoma."

40016186

➶

reach

"Given that oncolytic virus activates the RNA signaling pathway [23], we hypothesized that the knockdown of USP35 might enhance the anti-tumor immunity triggered by OVs."

40016186

USP35 activates immune response.

| 1

USP35 activates immune response. 1 / 1

| 1

➶

reach

"These findings suggest that targeting USP35 enhances anti-tumor immunity and boosts the efficacy of oncolytic virotherapy."

40016186

USP35 affects SREBF2

| 7

USP35 increases the amount of SREBF2.

| 4

USP35 increases the amount of SREBF2. 4 / 4

| 4

➶

reach

"Given that USP35 could stabilize BRPF1, we thus wondered whether USP35 could rely on BRPF1 to modulate SREBP2 expressions."

36357379

➶

reach

"Given that SREBP2 regulates a series of enzymes that sustain MVA metabolism activities, we observed that USP35 depletion could down-regulate the mRNA levels of SREBP2 downstream targets, named as MVA signature, including HMGCR, FDFT1, SQLE, MSMO1, FDPS and LSS (Fig. 6A)."

36357379

➶

| 7

➶

sparser

"USP35 directly interacts with ferroportin and maintain its protein stability to prevent iron overload and ferroptosis."

33931967

➶

sparser

"Together, these data indicate that USP35 can directly interact with FPN and functions as a deubiquitinase to maintain its protein stability."

33931967

➶

sparser

"In lung cancer cells, USP35 interacts directly with FPN1 to maintain its protein stability and prevent iron overload and ferroptosis ( xref )."

35478955

➶

sparser

"Further studies determined that USP35 directly interacted with ferroportin (FPN) and functioned as a deubiquitinase to maintain its protein stability."

33931967

➶

sparser

"FPN ubiquitination is required for its internalization and degradation, and Zhang et al identified the deubiquitinated role of USP35 in ovarian cancer cells. xref , xref Consistently, we found that USP35 directly interacted with FPN and functioned as a deubiquitinase to maintain its protein stability."

33931967

➶

sparser

"Conversely, the deubiquitinating enzyme USP35 interacts with SLC40A1 to maintain the protein stability of iron transporters, preventing the onset of ferroptosis in lung cancer [ xref ]."

38955112

➶

sparser

"First, the specific domain through which USP35 interacts with FPN remains unclear and demands further investigation."

33931967

USP35 affects PRKN

| 6

USP35 inhibits PRKN.

| 4

USP35 inhibits PRKN. 4 / 5

| 4

➶

reach

"For example, USP15, USP30, and USP35 are known to eliminate the ubiquitin- and parkin-mediated signals, consequently delaying or disrupting mitophagy (5)."

34674795

➶

reach

"Parkin mediated effects are further regulated by de-ubiquitinating enzymes, such as USP30 and USP35, which reportedly de-ubiquitinate Parkin substrates to antagonize mitophagy [XREF_BIBR] or Parkin dependent cell death [XREF_BIBR]."

26896558

➶

reach

"USP8, USP14, USP15, USP30, USP33, and USP35 have been shown to antagonize Parkin activity [[92], [93], [94], [95], [96], [97]]."

| 7

➶

sparser

"USP35 directly interacts with ferroportin and maintain its protein stability to prevent iron overload and ferroptosis."

33931967

➶

sparser

"Together, these data indicate that USP35 can directly interact with FPN and functions as a deubiquitinase to maintain its protein stability."

33931967

➶

sparser

"In lung cancer cells, USP35 interacts directly with FPN1 to maintain its protein stability and prevent iron overload and ferroptosis ( xref )."

35478955

➶

sparser

"Further studies determined that USP35 directly interacted with ferroportin (FPN) and functioned as a deubiquitinase to maintain its protein stability."

33931967

➶

sparser

33931967

➶

sparser

"Conversely, the deubiquitinating enzyme USP35 interacts with SLC40A1 to maintain the protein stability of iron transporters, preventing the onset of ferroptosis in lung cancer [ xref ]."

38955112

➶

sparser

"First, the specific domain through which USP35 interacts with FPN remains unclear and demands further investigation."

33931967

MYC affects USP35

| 7

MYC binds USP35. 7 / 7

| 7

➶

sparser

"Co-immunoprecipitation (Co-IP) experiments in 293 T co-transfected with Myc-USP35 and Flag-tagged RIG-I, MAVS, or TBK1 showed that USP35 strongly interacted with MAVS (Fig. xref )."

40016186

➶

sparser

36357379

➶

sparser

"We transfected Flag-Snail1 and HA-Ub, together with Myc-USP35 or empty vector, into HEK293T and MKN-45 cells and performed a Co-IP assay."

38250150

➶

sparser

38250150

➶

sparser

"We co-expressed MAVS-Flag, USP35-Myc, and HA-Ub or HA-Ub K63O (K63 only) in 293 T. The results showed that USP35 removed the K63-type ubiquitination of MAVS (Fig. xref )."

40016186

➶

sparser

38250150

➶

sparser

"Restoration of Myc-USP35 in USP35-depleted A375 inhibited TBK1 and IRF3 activation upon RNA virus stimulation (Supplementary Fig. xref )."

40016186

CDH1 affects USP35

| 3 4

CDH1 binds USP35.

| 2 4

USP35 binds CDH1. 6 / 6

| 2 4

➶

reach

"Interestingly, we also observed that USP35 could bind to CDH1."

29449677

➶

sparser

29449677

➶

reach

"USP35 can bind to CDH1 and restore Aurora B levels that have been reduced by CDH1 induced ubiquitination, suggesting that USP35 counteracts the APC CDH1 -mediated ubiquitination of Aurora B."

29449677

➶

sparser

29449677

➶

sparser

32201366

➶

sparser

"Interestingly, we also observed that USP35 could bind to CDH1 (Fig. xref )."

29449677

CDH1 ubiquitinates USP35.

| 1

CDH1 leads to the ubiquitination of USP35. 1 / 1

| 1

➶

reach

"However, CDH1 had no effect on the levels of USP35 protein and could not induce the ubiquitination of USP35."

29449677

BRPF1 affects USP35

3 | 3 1

BRPF1 binds USP35.

3 | 2 1

BRPF1 binds USP35. 3 / 6

3 | 2 1

➶

sparser

"First of all, the co-immunoprecipitation (co-IP) analysis with an anti-USP35 indicated that USP35 could directly interact with BRPF1, implicating the endogenous interactions (Fig. xref )."

36357379

➶

reach

"USP35 interacts with and deubiquitinates BRPF1 in PRAD cells."

36357379

➶

reach

"Considering that epigenetic deregulation contributes to PRAD progression and BRPF1 is less reported in PRAD, we thus decided to confirm the associations between USP35 and BRPF1."

36357379

BRPF1 inhibits USP35.

| 1

BRPF1 inhibits USP35. 1 / 1

| 1

➶

reach

"We generated the C4-2b-derived tumor model and found that targeting BRPF1 could significantly suppress USP35 in vivo PRAD growth, as shown by tumor volumes and weight (Fig. 6F–H)."

36357379

BIRC5 affects USP35

2 | 2 3

BIRC5 binds USP35. 5 / 7

2 | 2 3

➶

reach

"USP35/USP38 interacted with and deubiquitinated survivin."

34438346

➶

sparser

"To investigate the mechanism by which USP35 regulates the protein stability of survivin, we next tested whether USP35 interacts with survivin."

34438346

➶

reach

"Our work revealed that USP35 and its orthologous gene USP38 interacted with and deubiquitinated survivin, which in turn stabilized the survivin protein."

34438346

➶

sparser

"USP35 interacted with survivin and promoted the deubiquitination of survivin."

34438346

➶

sparser

"Interestingly, we found that USP35 interacted with survivin, which is also an IAP."

34438346

USP35 affects cell growth

| 6

USP35 activates cell growth.

| 4

USP35 activates cell growth. 4 / 4

| 4

➶

reach

"Accordingly, (+)-JQ-1 treatment blocked the increase in cell growth induced by USP35 overexpression (Fig. 6E)."

39820080

➶

reach

"Conversely, USP35 overexpression in MCF-7 and ZR-75-1 cell (Fig. 2D) partially rescued cell growth inhibited by RSL3 treatment (Fig. 2E)."

39820080

➶

reach

"Depletion of USP35 promotes ferroptosis and suppresses lung cancer cell growth and tumor progression [16]."

40016186

➶

reach

"Furthermore, BRD4 overexpression also partially rescued the cell growth inhibition induced by USP35 knockdown (Fig. 6C)."

39820080

USP35 inhibits cell growth.

| 2

USP35 inhibits cell growth. 2 / 2

| 2

➶

reach

"So we speculate that USP35 can inhibit cancer cell growth through inhibiting NF-kappaB pathway by stabilizing ABIN-2."

26348204

➶

reach

"These results suggest that USP35 can inhibit cancer cell growth efficiently."

26348204

USP35 affects Reactive Oxygen Species

| 6

USP35 decreases the amount of Reactive Oxygen Species.

| 4

USP35 decreases the amount of Reactive Oxygen Species. 4 / 4

| 4

➶

reach

"In addition, BRD4 overexpression dramatically decreased Lipid ROS level induced by USP35 knockdown in two cell lines (Fig. 6B, Supplementary Fig. 1F)."

39820080

➶

reach

"Furthermore, silencing USP35 increased Lipid ROS levels in ER+ breast cancer cells, which were also attenuated by Ferro-1 treatment (Fig. 1D, Supplementary Fig. 1A)."

39820080

➶

reach

"We found that SLC7A11 overexpression partially reduced the increase in Lipid ROS level induced by USP35 knockdown (Fig. 3D, Supplementary Fig. 1D)."

39820080

➶

reach

"Meanwhile, knockdown of USP35 dramatically enhanced Lipid ROS level induced by Erastin or RSL3 treatment in MCF-7 and ZR-75-1 cells (Fig. 2B, Supplementary Fig. 1B)."

39820080

USP35 inhibits Reactive Oxygen Species.

| 2

USP35 inhibits Reactive Oxygen Species. 2 / 2

| 2

➶

reach

"Collectively, these findings suggest that excessive USP35 enhances the capacity of hUC-MSCs and hUC-MSC-EVs to reduce apoptosis and ROS stress in cocultured SH-SY5Y OGD/R cells."

39406943

➶

reach

"We then investigated whether USP35 overexpression could potentiate the function of hUC-MSC and hUC-MSC-EV in alleviating apoptosis and reducing ROS stress in SH-SY5Y OGD/R cells."

39406943

USP35 affects NPPA

| 6

NPPA binds USP35. 6 / 6

| 6

➶

sparser

"The production lots presented in Table xref were also analysed for the presence of the bacterial lipopolysaccharide (LPS), which is a membrane component of Gram‐negative bacteria that could act as endotoxin, according to the US Pharmacopeia method based on the use of amoebocyte lysate from the horseshoe crab (USP35‐NF30, xref ) and all the samples analysed tested negative."

32625902

➶

sparser

"At present, CRG has already been included in United States Pharmacopeia 35-National Formulary 30S1 (USP35-NF30S1), British Pharmacopoeia 2012 (BP2012) and European Pharmacopoeia 7.0 (EP7.0), implying that CRG may have a promising future as a pharmaceutical excipient."

36005525

➶

sparser

"Today, CRGs, due to the safety of the application (included in (USP35-NF30S1), (BP2012), and (EP7.0)), have a wide range of applications in the biomedical field as an excipient."

36555404

➶

sparser

"It has been confirmed that each mL of 0.5 N sodium hydroxide was equivalent to 301.5 mg (0.5 N) benzonatate in US pharmacopoeia (USP35–NF30), which indicated that each mL of 0.5 N benzonatate was equi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

31129533

➶

sparser

"At present, CRG has been included in the United States Pharmacopeia 35-National Formulary 30S1 (USP35-NF30S1), the British Pharmacopoeia 2012 (BP2012), and the European Pharmacopoeia 7.0 (EP7.0), implying that CRG may have a promising future as a pharmaceutical excipient."

32397584

➶

sparser

"Dosage units are defined as dosage forms containing a single dose or part of a dose of drug substance in each unit ( USP35-NF30, 2012 )."

24157343

USP35 affects NFkappaB

| 3 1

USP35 inhibits NFkappaB. 4 / 6

| 3 1

➶

reach

"Collectively, our data indicated that miR let-7a-regulated USP35 can inhibit NF-kappaB activation by deubiquitination and stabilization of ABIN-2 protein and eventually inhibit cell proliferation."

26348204

➶

reach

"XREF_BIBR In addition, miR-let-7a was shown to regulate USP35 expression, which then inhibited NF-kappaB activation by deubiquitination and stabilization of TNIP2 protein."

32606763

➶

reach

"USP35 activated by miR let-7a inhibits cell proliferation and NF-kappaB activation through stabilization of ABIN-2."

26348204

➶

sparser

"Functionally, both ABIN-2 and USP35 could inhibit TNFα-induced NF-κB activation and overexpression of ABIN-2 alleviated USP35-loss induced activation of NF-κB. Collectively, our data indicated that miR let-7a-regulated USP35 can inhibit NF-κB activation by deubiquitination and stabilization of ABIN-2 protein and eventually inhibit cell proliferation."

26348204

USP35 affects Interferon

| 6

USP35 inhibits Interferon.

| 3

USP35 inhibits Interferon. 3 / 3

| 3

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"Our findings further underscore the role of USP35 in negatively regulating the MAVS-TBK1-IRF3 signaling pathway, and the knockdown of USP35 enhances type I interferon and inflammation-related factor expression in response to cytoplasmic RNA virus or RNA analog.MAVS is an essential adapter protein in the RLR pathway and plays a key role in the production of type I IFN [29]."

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USP35 activates ESR. 4 / 4

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"USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis."

39820080

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"Similar effects have been observed in breast cancer, where USP35 enhances tumorigenesis by stabilizing estrogen receptor α (ERα), leading to increased proliferation and metastasis [37]."

40188027

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"Moreover, USP15 and USP35 also mediate ERα protein stability and promote breast cancer tamoxifen resistance in human breast cancer [ 51 , 52 ]."

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"Today, CRGs, due to the safety of the application (included in (USP35-NF30S1), (BP2012), and (EP7.0)), have a wide range of applications in the biomedical field as an excipient."

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"Dosage units are defined as dosage forms containing a single dose or part of a dose of drug substance in each unit ( USP35-NF30, 2012 )."

24157343

MicroRNAs affects USP35

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MicroRNAs activates USP35.

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MicroRNAs activates USP35. 4 / 4

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"The molecular pathways by which miR let-7a up-regulates USP35 need to be further investigated."

26348204

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"These findings indicate that USP35 up-regulated by miR let-7a potentially functions as a tumor suppressor and inhibits tumor growth."

26348204

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"USP35 activated by miR let-7a inhibits cell proliferation and NF-kappaB activation through stabilization of ABIN-2."

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USP35 activates cell death. 3 / 3

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"Taken together, USP35 plays a vital role in resistance to cisplatin-induced cell death through the overexpression of BIRC3."

35022505

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39820080

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"To further explore the mechanism of USP35 action in ER+ breast cancer, we investigated whether USP35 promotes the growth of ER+ breast cancer by inhibiting cell death."

39820080

USP35 inhibits cell death.

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USP35 inhibits cell death. 2 / 2

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2 | 1

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"USP35 interacts directly with ribosome binding protein 1 (RRBP1) to prevent its degradation by proteolytic enzymes ( xref )."

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USP35 inhibits RRBP1.

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USP35 inhibits RRBP1. 2 / 2

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"Moreover, the expression of USP35 is positively correlated with poor prognosis of non-small cell lung cancer (NSCLC) and represses endoplasmic reticulum stress-induced apoptosis by stabilizing RRBP1 [36]."

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"Furthermore, USP35 attenuates endoplasmic reticulum stress-induced apoptosis by stabilizing RRBP1 in non-small cell lung cancer cells (25)."

37594129

USP35 affects IRF3

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USP35 binds IRF3.

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USP35 binds IRF3. 3 / 3

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"These results indicate that AXIN1 potentially functions as a crucial scaffold to facilitate the interaction between USP35 and IRF3."

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"Consistently, AXIN1 knockdown attenuated the interaction between IRF3 and USP35, but not the interaction between IRF3 and any other USPs (Supplementary Fig. xref )."

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"In this study, we highlighted the SREBP2-dependent MVA crosstalk is activated by USP35/BRFP1 axis to drive tumor progression."

36357379

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"We would design other assays in the future to confirm whether USP35-mediated MVA metabolism could influence the progression of Castration-Resistant Prostate Cancer (CRPC)."

36357379

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"Taken together, these data implicated that USP35/BRPF1 axis could modulate MVA crosstalk in PRAD in a SREBP2-dependent manner."

36357379

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"Meanwhile, USP35 could activate MVA signature and this effect could be completely abolished by BRPF1 KD (Fig. 6B)."

36357379

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"Thus, USP35/BRPF1 axis modulated the MVA crosstalk via induction of SREBP2."

36357379

Infections affects USP35

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Infections increases the amount of USP35.

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Infections increases the amount of USP35. 3 / 3

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"Helicobacter pylori infection increased USP35 and Snail1 expression levels."

38250150

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"As shown in Fig. 8L, infection with H. pylori increased USP35 and Snail1 protein levels, indicating that H. pylori infection contributes to the upregulation of USP35 and Snail1."

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37993419

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"USP35 stabilizes ribosome binding protein 1 (RRBP1) and reduces endoplasmic reticulum stress-induced apoptosis in NSCL [190]."

35884607

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"For example, USP35 can reduce the endoplasmic reticulum stress-induced apoptosis by stabilizing ribosomal binding protein 1 (RRBP1) (Garcia-Santisteban et al., 2013; Wang et al., 2022)."

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"Furthermore, USP35 attenuates endoplasmic reticulum stress-induced apoptosis by stabilizing RRBP1 in non-small cell lung cancer cells (25)."

37594129

USP35 affects activation

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USP35 inhibits activation. 4 / 4

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"Taken together, these results suggest that USP35 could inhibit TNFα-induced NF-κB activation by stabilizing ABIN-2 protein."

26348204

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"USP35 inhibits TNFα-induced NF-κB activation through stabilizing ABIN-2 protein."

26348204

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"When activated by miR let-7a, USP35 inhibits NF-κB activation by deubiquitinating and stabilizing ABIN-2, which subsequently inhibits tumor growth xref ."

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"In addition, overexpression of USP35 inhibited TNFα-induced NF-κB activation by deubiquitination and stabilization of TNFAIP3 interacting protein 2 (ABIN-2)."

26348204

USP35 affects RIGI

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USP35 inhibits RIGI.

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USP35 inhibits RIGI. 3 / 3

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"IFN activates the expression of interferon-stimulated genes (ISGs), which contain ISRE (interferon-stimulated response element) elements in the promoters [ xref ]. we also found that USP35 also inhibited RIG-I or MAVS-induced ISRE-Luc activity (Fig. xref )."

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"Using the luciferase reporter assay, we found that USP35 inhibits RIG-I and MAVS-mediated IFN-β reporter gene expression."

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"Furthermore, USP35 was found to inhibit RIG-I, but not TBK1-activated IFNβ-Luc expression (Fig. 2B), suggesting that the regulation is at the layer of RIG-I-MAVS."

40016186

USP35 ubiquitinates RIGI.

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USP35 ubiquitinates RIGI. 1 / 1

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"In contrast, both USP35-WT and USP35-CA had no significant effect on the ubiquitination of RIG-I or TBK1 (Fig. 4B, C), indicating that USP35 specifically deubiquitinates MAVS."

40016186

USP35 affects PI3K

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USP35 activates PI3K.

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USP35 activates PI3K. 3 / 3

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"Our data also demonstrate that USP35 promotes HCC development by stabilizing ABHD17C and activates the PI3K/AKT pathway.The oncogenic function of USP35 in other cancers has been well characterized."

37993419

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"USP35 promotes HCC development by stabilizing ABHD17C and activating the PI3K/AKT signaling pathway."

37993419

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"Taken together, these observations indicate that the increased expression of USP35 and ABHD17C in HCC may help activate the PI3K/AKT pathway."

37993419

USP35 increases the amount of PI3K.

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USP35 increases the amount of phosphorylated PI3K. 1 / 1

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"To decide whether the oncogenic function of USP35 in HCC cells relies on ABHD17C, we overexpressed ABHD17C in USP35-deficient Hep3B and SNU449 cells and found that ABHD17C overexpression rescued the reduced levels of p-PI3K and p-AKT caused by USP35 knockdown (Fig. 5A, B)."

37993419

USP35 affects Neoplasm Metastasis

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USP35 activates Neoplasm Metastasis. 4 / 4

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"These results suggest that USP35 relies on DUB activity to promote GC metastasis in vivo."

38250150

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"USP35 promotes GC metastasis in vivo."

38250150

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"To further explore whether USP35 promotes cell metastasis in vivo, we collected BGC-823 cells stably overexpressing WT-USP35 or the USP35-C450A mutant (Fig. 7A) and performed experiments in nude mice by injecting the stably overexpressing cells into the tail vein."

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"Knockdown of USP35 promoted cancer cell ferroptosis and inhibited cancer cell growth and metastasis (50)."

40224981

USP35 affects Flag

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USP35 binds Flag. 4 / 4

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"To explore the effects of Ser613 phosphorylation on USP35 localization and function, MCF-7 and T-47D cells were engineered to express vector alone, Flag-USP35 WT , Flag-USP35 S613A , and Flag-USP35 S613E (Fig. xref )."

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"Consistent with this, ectopically expressed Flag-USP35 was associated with endogenous Aurora B in HEK293T and HeLa cells, and conversely, endogenous USP35 was precipitated efficiently by HA-Aurora B affinity purification (Supplementary Fig. xref , xref , c)."

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USP35 activates AKT. 2 / 2

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"Taken together, these observations indicate that the increased expression of USP35 and ABHD17C in HCC may help activate the PI3K/AKT pathway."

37993419

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"Our data also demonstrate that USP35 promotes HCC development by stabilizing ABHD17C and activates the PI3K/AKT pathway.The oncogenic function of USP35 in other cancers has been well characterized."

37993419

USP35 increases the amount of AKT.

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USP35 increases the amount of phosphorylated AKT. 1 / 1

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37993419

USP35 binds AKT.

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AKT binds USP35. 1 / 1

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"These data indicate that AKT interacts with USP35 and phosphorylates USP35 at Ser613."

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Flag affects USP35

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USP35 binds Flag. 4 / 4

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"To test whether Ser613 can be phosphorylated by AKT, Flag-USP35 WT or Flag-USP35 S613A vector was cotransfected with the activated AKT mutant plasmid into 293 T cells."

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USP35 affects autophagy of mitochondrion

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USP35 inhibits autophagy of mitochondrion. 3 / 3

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"USP15, USP30 and USP35 inhibit mitophagy by removing the ubiquitin signal from Parkin targets [46–48]."

38491202

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"In addition, the short form of USP35 impairs mitophagy through Parkin deubiquitination [154]."

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USP35 inhibits Melanoma. 2 / 2

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"Knockdown of USP35 enhances the anti-tumor immunity of malignant melanoma to oncolytic virotherapy."

40016186

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"The knockdown of USP35 enhances the anti-tumor immunity of oncolytic viruses in malignant melanoma."

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USP35 activates Melanoma.

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USP35 activates Melanoma. 1 / 1

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"Importantly, depletion of USP35 significantly enhances the anti-tumor immunity and synergizes with oncolytic virotherapy to suppress xenograft tumor growth of melanoma cells."

40016186

USP35 affects Histone_H3

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USP35 phosphorylates Histone_H3.

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USP35 inhibits BIRC3.

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USP35 inhibits BIRC3. 2 / 2

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"Overexpression of USP35 in H460 cells increased the abundance of BIRC3, while USP35 knockdown in Anip973 cells decreased BIRC3 abundance."

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"USP35 resists cell apoptosis by stabilizing anti-apoptotic factor BIRC3 and relieves endoplasmic reticulum stress (ERS) by deubiquitinating RRBP1 [20, 22]."

36864055

USP35 activates BIRC3.

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USP35 activates BIRC3. 1 / 1

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"Overexpression of USP35 in H460 cells increased the abundance of BIRC3, while USP35 knockdown in Anip973 cells decreased BIRC3 abundance."

35022505

STUB1 affects USP35

1 | 2

STUB1 binds USP35.

"Using different deletion mutant of USP35, we found that USP35 interacts with ERα via its USP35 domain (data not shown)."

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"The activated USP35 interacts with ERα, boosting its transcriptional activity, which diminishes the effectiveness of tamoxifen and fulvestrant treatments [ xref ]."

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CXCR3 affects USP35

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CXCR3 binds USP35.

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CXCR3 binds USP35. 2 / 2

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"These findings collectively demonstrate the oncogenic role of the USP35-CXCR3 axis in JeKo-1 MCL cells."

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"The USP35-CXCR3 Axis plays an oncogenic role in JeKo-1 mantle cell lymphoma cells."

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CXCR3 activates USP35.

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CXCR3 activates USP35. 1 / 1

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ABHD17C affects USP35

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USP35 binds ABHD17C. 3 / 3

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"USP35 can interact with and stabilize ABHD17C by inhibiting its ubiquitination."

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"Knockdown of USP35 increases the activation of the STING signaling pathway [134] ."

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USP35 affects paclitaxel

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USP35 inhibits paclitaxel.

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USP35 inhibits paclitaxel. 1 / 1

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36864055

USP35 activates paclitaxel.

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USP35 activates paclitaxel. 1 / 1

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"Their study also raises a question whether targeting USP35 will modulate Taxol response in cancers."

36864055

USP35 affects oxaliplatin

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USP35 activates oxaliplatin. 2 / 2

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"It has been shown that USP35 overexpression enhances CRC cell proliferation and resistance to oxaliplatin and 5-FU[85]."

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38250150

USP35 affects aurora subfamily

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USP35 binds aurora subfamily. 2 / 2

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"We then investigated whether USP35 overexpression could potentiate the function of hUC-MSC and hUC-MSC-EV in alleviating apoptosis and reducing ROS stress in SH-SY5Y OGD/R cells."

39406943

USP35 activates OGD/R.

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"Additionally, USP35 knockdown enhanced the expression of IFN-β, CXCL10, and ISG15 triggered by RNA viruses or exogenous RNA-3pRNA."

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USP35 increases the amount of CDH2. 1 / 1

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"Silencing USP35 significantly reduced N-cadherin levels and increased E-cadherin expression (p < 0.01), indicating its role in regulating EMT in KIRC cells (F ig."

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USP35 activates CDH2.

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USP35 activates CDH2. 1 / 1

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"We also searched the MVP database to validate that the USP35-GAB2 region is associated with multiple blood pressure-related phenotypes."

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"However, we found that the variants in the USP35-GAB2 region identified by previous genome-wide association studies (GWAS) differed from what we identified in LOP."

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FOXM1 affects USP35

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FOXM1 increases the amount of USP35. 2 / 2

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"Finally, the transcription factor FoxM1 promotes the expression of USP35, as well as that of Aurora B, during the cell cycle."

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USP35 affects VIM

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FUS affects USP35

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FUS binds USP35. 1 / 1

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"FUS interacted with USP35 to promote its mRNA stability, thereby positively regulating VEGFA expression."

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ESR affects USP35

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"Estrogen enhanced USP35 protein levels by downregulating USP35 targeting miRNA-140-3p and miRNA-26a-5p."

34131114

IndraLab

Statements

USP35 affects FUCA1

USP35 binds FUCA1.

FUCA1 binds USP35. 10 / 28

USP35 deubiquitinates FUCA1.

USP35 deubiquitinates FUCA1. 6 / 6

Mutated USP35 deubiquitinates FUCA1. 1 / 1

USP35 activates FUCA1.

USP35 activates FUCA1. 4 / 4

USP35 decreases the amount of FUCA1.

USP35 decreases the amount of FUCA1. 2 / 2

USP35 inhibits FUCA1.

USP35 inhibits FUCA1. 1 / 1

USP35 affects MAVS

USP35 binds MAVS.

USP35 binds MAVS. 10 / 25

USP35 binds MAVS and K63. 1 / 1

USP35 inhibits MAVS.

USP35 inhibits MAVS. 4 / 4

USP35 deubiquitinates MAVS.

USP35 deubiquitinates MAVS. 3 / 3

USP35-C450A deubiquitinates MAVS. 1 / 1

USP35 decreases the amount of MAVS.

USP35 decreases the amount of MAVS. 1 / 1

USP35 activates MAVS.

USP35 activates MAVS. 1 / 1

USP35 affects cell population proliferation

USP35 activates cell population proliferation.

USP35 activates cell population proliferation. 10 / 20

USP35 inhibits cell population proliferation.

USP35 inhibits cell population proliferation. 10 / 15

FUCA1 affects USP35

FUCA1 binds USP35.

FUCA1 binds USP35. 10 / 28

FUCA1 activates USP35.

FUCA1 activates USP35. 3 / 3

FUCA1 inhibits USP35.

FUCA1 inhibits USP35. 1 / 1

USP35 affects TNIP2

USP35 binds TNIP2.

USP35 binds TNIP2. 8 / 12

USP35 deubiquitinates TNIP2.

USP35 deubiquitinates TNIP2. 4 / 5

Modified USP35 leads to the deubiquitination of TNIP2. 1 / 1

USP35 activates TNIP2.

USP35 activates TNIP2. 2 / 4

USP35 inhibits TNIP2.

USP35 inhibits TNIP2. 1 / 2

USP35 increases the amount of TNIP2.

Modified USP35 increases the amount of TNIP2. 1 / 1

USP35 increases the amount of TNIP2. 1 / 1

USP35 ubiquitinates TNIP2.

USP35 leads to the ubiquitination of TNIP2. 1 / 1

USP35 decreases the amount of TNIP2.

USP35 decreases the amount of TNIP2. 1 / 1

MAVS affects USP35

USP35 binds MAVS. 10 / 25

USP35 binds MAVS and K63. 1 / 1

USP35 affects SNAI1

USP35 binds SNAI1.

USP35 binds SNAI1. 9 / 9

USP35 increases the amount of SNAI1.

USP35 increases the amount of SNAI1. 4 / 4

USP35 bound to SNAI1 increases the amount of SNAI1. 1 / 1

USP35 deubiquitinates SNAI1.

USP35 deubiquitinates SNAI1. 5 / 5

USP35 decreases the amount of SNAI1.

USP35 decreases the amount of SNAI1. 2 / 2

USP35 activates SNAI1.

USP35 activates SNAI1. 2 / 2

USP35 affects STING1

USP35 binds STING1.

USP35 binds STING1. 3 / 9

USP35 inhibits STING1.

USP35 inhibits STING1. 6 / 6

USP35 deubiquitinates STING1.

USP35 deubiquitinates STING1. 5 / 5

USP35 dephosphorylates STING1.

USP35 leads to the dephosphorylation of STING1. 1 / 1