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The OTUD6B-LIN28B-MYC axis determines the proliferative state in multiple myeloma

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Item Type:Article
Title:The OTUD6B-LIN28B-MYC axis determines the proliferative state in multiple myeloma
Creators Name:Paulmann, C. and Spallek, R. and Karpiuk, O. and Heider, M. and Schäffer, I. and Zecha, J. and Klaeger, S. and Walzik, M. and Öllinger, R. and Engleitner, T. and Wirth, M. and Keller, U. and Krönke, J. and Rudelius, M. and Kossatz, S. and Rad, R. and Kuster, B. and Bassermann, F.
Abstract:Deubiquitylases (DUBs) are therapeutically amenable components of the ubiquitin machinery that stabilize substrate proteins. Their inhibition can destabilize oncoproteins that may otherwise be undruggable. Here, we screened for DUB vulnerabilities in multiple myeloma, an incurable malignancy with dependency on the ubiquitin proteasome system and identified OTUD6B as an oncogene that drives the G1/S-transition. LIN28B, a suppressor of microRNA biogenesis, is specified as a bona fide cell cycle-specific substrate of OTUD6B. Stabilization of LIN28B drives MYC expression at G1/S, which in turn allows for rapid S-phase entry. Silencing OTUD6B or LIN28B inhibits multiple myeloma outgrowth in vivo and high OTUD6B expression evolves in patients that progress to symptomatic multiple myeloma and results in an adverse outcome of the disease. 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.
Keywords:Cell Cycle, Deubiquitylases, Multiple Myloma, RNA Binding Proteins, Ubiquitin, Animals, Mice
Source:EMBO Journal
ISSN:0261-4189
Publisher:Nature Publishing Group
Page Range:e110871
Date:5 September 2022
Official Publication:https://doi.org/10.15252/embj.2022110871
PubMed:View item in PubMed

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