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

Carmen Paulmann, Ria Spallek, Oleksandra Karpiuk, Michael Heider, Isabell Schäffer, Jana Zecha, Susan Klaeger, Michaela Walzik, Rupert Öllinger, Thomas Engleitner, Matthias Wirth, Ulrich Keller, Jan Krönke, Martina Rudelius, Susanne Kossatz, Roland Rad, Bernhard Kuster, Florian Bassermann

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Article numbere110871
JournalEMBO Journal
Volume41
Issue number20
DOIs
StatePublished - 17 Oct 2022

Keywords

  • RNA binding proteins
  • cell cycle
  • deubiquitylases
  • multiple myloma
  • ubiquitin

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