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UCHL1 activates HIF1. 26 / 28
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"We then examined the molecular mechanisms underlying the upregulation of HIF-1 by UCHL1."
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"Our study reveals that integrin α6β4 plays a critical role in promoting the aggressiveness of TNBC by upregulating the expression of the protein tyrosine phosphatase PTPRZ1 through UCHL1-mediated Hif-1α signaling (Figure 8)."
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"Ubiquitin C-terminal hydrolase-L1 (UCHL1) can activate HIF-1α, which is a new tumor therapeutic target (16)."
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"Then UCHL1 and HIF-1α inhibitor and siRNA targeting SRY-box transcription factor 9 (SOX9) were used to block UCHL1, HIF-1α and SOX9, respectively."
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"We subsequently investigated the influence of the UCHL1 mediated activation of HIF-1 on tumour malignancy."
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"The deubiquitinating enzymes USP20, USP8 and UCHL1 can modulate the HIF-1α level and stability, and regulate VEGF expression (32)."
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"UCHL1 deubiquitinates HIF-1alpha protein [ 31 ] , upregulates HIF-1 activity , and mediates cellular protection under hypoxia ."
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"The inhibitor of UCHL1 , LDN-57444 ( Figure 6J ) , blocks the UCHL1-HIF1 axis and therefore inhibits HIF-1 activity as UCHL1 deubiquitinate and stabilizes HIF-1alpha ."
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"Deubiquitinating enzymes such as UCHL1 promote HIF1 activity under normoxic and hypoxic conditions by disrupting ubiquitin-mediated proteasomal degradation of HIF1α [9]."
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"Because HIF-1 activity is known to be regulated at multiple steps, we first aimed to identify the key regulatory mechanism in the UCHL1 mediated activation of HIF-1 in EMT6 cells."
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"First, we performed a luciferase assay using the 5HRE-luc reporter gene 43, which expresses luciferase bioluminescence in a HIF-1-dependent manner, in order to test whether UCHL1 enhanced HIF-1 activity in EMT6 cells."
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"The forced expression of UCHL1 significantly enhanced HIF-1 activity regardless of the oxygen conditions."
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"Of note, only the HIF/hypoxia-responsive pro-fibrotic genes, αSMA and TIMP1, were induced by UCHL1 overexpression, consistent with the model of UCHL1 increasing HIF1α levels and HIF activity (Figure 3D)."
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"These results collectively indicate that UCHL1 stabilizes HIF-1alpha protein, and elicits HIF-1 activity in a deubiquitinating activity dependent manner in EMT6 cells."
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"These results suggested that the expression of UCHL1 would lead to a poor prognosis by activating HIF-1; therefore, it could be a useful prognostic marker."
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"In the present study, we provided direct evidence to show that UCHL1 was responsible for the deubiquitination of HIF-1alpha and upregulated HIF-1 activity."
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"In the present study, we found that the UCHL1 mediated activation of HIF-1 through the deubiquitination of HIF-1alpha protein induced the antioxidant and radioresistant properties of cancer cells by producing an antioxidant, GSH, through the so called carbohydrate metabolic reprogramming and subsequent activation of the pentose phosphate pathway."
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"In order to fully elucidate the molecular mechanisms underlying the UCHL1 mediated upregulation of HIF-1 activity, further investigation is needed."
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"In addition, UCHL1 enhances the activity of hypoxia-inducible factor 1-alpha (HIF1α) by regulating its degradation, which is ubiquitinated by von Hippel–Lindau (pVHL) E3 ubiquitin ligase."
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"Using an elegant screening approach to identify factors that would lead to HIF-1 transcriptional activity under normoxic conditions, Goto et al. recently identified the ubiquitin C-terminal hydrolase-L1 (UCHL1) as a HIF-1 deubiquitinating enzyme that promotes HIF-1 activity under normoxic and hypoxic conditions by preventing VHL mediated degradation of HIF-1 (XREF_FIG)."
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"In this study, we implicate UCHL1-mediated Hif-1α nuclear accumulation in integrin α6β4-regulated PTPRZ1 expression that drives the invasive phenotype of TNBC cells."
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"The inhibitor of UCHL1, LDN-57444 (XREF_FIG J), blocks the UCHL1-HIF1 axis and therefore inhibits HIF-1 activity as UCHL1 deubiquitinate and stabilizes HIF-1alpha."
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"To address whether integrin β4 upregulation of UCHL1 expression contributes to increased Hif-1α nuclear accumulation, we treated BT549-β4 cells with different doses of UCHL1 inhibitor LDN57444 for 48 h prior to immunoblot analysis of nuclear extracts."
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"UCHL1 upregulates HIF-1 activity."
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"We performed a luciferase assay using the 5HREp-luc reporter gene, which expressed firefly luciferase under the control of 5HREp XREF_BIBR XREF_BIBR, to examine whether UCHL1 induced HIF-1 activity."
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"These results clearly indicated that UCHL1 upregulated HIF-1 activity in various cancer cell lines."
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