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OTUD6B binds LIN28B. 19 / 26
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"Thus, we link proteolytic ubiquitylation with post‐transcriptional regulation and nominate OTUD6B as a potential mediator of the MGUS‐multiple myeloma transition, a central regulator of MYC, and an actionable vulnerability in multiple myeloma and other tumors with an activated OTUD6B‐LIN28B axis."
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"First, we confirmed specific bi‐directional binding between LIN28B and OTUD6B using different members of the OTU DUB family as controls (Fig EV3D and E)."
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"To this end, we compared binding of OTUD6B to LIN28B in G1/S synchronized MM1.S cells and cells released from the cell cycle block."
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"These experiments revealed that binding of OTUD6B to LIN28B specifically occurs at G1/S (Fig 3A)."
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"We next investigated whether LIN28B is a G1/S‐specific deubiquitylation substrate of OTUD6B. To this end, we compared binding of OTUD6B to LIN28B in G1/S synchronized MM1."
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"These experiments revealed that binding of OTUD6B to LIN28B specifically occurs at G1/S (Fig  xref )."
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"Given the strong implication of the OTUD6B‐LIN28B axis in cell cycle progression, we next performed in vivo xenograft experiments with human MM cells to further validate this nexus as a central vulnerability in MM."
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"These data distinguish the OTUD6B‐LIN28B DUB‐substrate pair as central dependency in MM cells in vitro and in vivo ."
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"To understand how the OTUD6B‐LIN28B axis regulates the G1/S‐transition, we performed RNA‐Seq experiments in MM cells, which were transduced with shRNAs against OTUD6B, LIN28B or respective controls."
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"Strikingly, we found a significant downregulation of prominent MYC targets (Mootha et al ,  xref ; Subramanian et al ,  xref ) in OTUD6B and LIN28B depleted MM cells, suggesting a direct impact of the OTUD6B‐LIN28B axis on MYC expression and activity (Fig  xref , and Appendix Fig  xref A)."
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"From a cell biological point of view, the OTUD6B‐LIN28B nexus links proteolytic ubiquitylation to mRNA biogenesis and eventually directs MYC activity to the G1/S cell cycle transition, a previously unappreciated crosstalk (Hildebrandt et al ,  xref )."
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"The development of OTUD6B inhibitors thus seems warranted and we here present the biological and clinical framework and rationale from which to further approach this effort to improve the outcome of MM and potentially other tumors with an activated OTUD6B‐LIN28B axis."
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"When MCTS1 was knocked down, the binding of OTUD6B to LIN28B was also impaired ( Fig. 3 A)."
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"Since we confirmed that MCTS1 modulates the stability of LIN28B via interacting with OTUD6B and enhancing its deubiquitination, we further explored whether it regulates LSCC growth via the OTUD6B-LIN2[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"These findings imply that MCTS1 could enhance LSCC proliferation partially via the OTUD6B-LIN28B axis."
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"Therefore, we hypothesized that the OTUD6B-LIN28B is another downstream axis mediating the tumorigenic effect of MCTS1 in LSCC."
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"In summary, this study revealed that MCTS1 could enhance LSCC proliferation partially via the OTUD6B-LIN28B axis."
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"In G1/S synchronized AMC–HN–8 and TU177 cells, the binding between OTUD6B and LIN28B was confirmed."
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"When MCTS1 was knocked down, the binding of OTUD6B to LIN28B was also impaired ( Fig. 3 A)."
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