生物
多发性骨髓瘤
基因沉默
癌症研究
泛素
小RNA
细胞周期
蛋白酶体
调节器
细胞生物学
Carfilzomib公司
硼替佐米
细胞
遗传学
免疫学
基因
作者
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 Küster,Florian Bassermann
标识
DOI:10.15252/embj.2022110871
摘要
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.
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