The OTUD6B-LIN28B-MYC axis determines the proliferative state in multiple myeloma.
RNA binding proteins
cell cycle
deubiquitylases
multiple myloma
ubiquitin
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
17 10 2022
17 10 2022
Historique:
revised:
27
07
2022
received:
07
02
2022
accepted:
01
08
2022
pubmed:
6
9
2022
medline:
19
10
2022
entrez:
5
9
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36059274
doi: 10.15252/embj.2022110871
pmc: PMC9574752
doi:
Substances chimiques
LIN28B protein, human
0
MYC protein, human
0
MicroRNAs
0
Proto-Oncogene Proteins c-myc
0
RNA-Binding Proteins
0
Ubiquitins
0
Endopeptidases
EC 3.4.-
OTUD6B protein, human
EC 3.4.-
Proteasome Endopeptidase Complex
EC 3.4.25.1
Banques de données
GEO
['GSE24080', 'GSE9782']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e110871Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
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