Imaging-Based Screening of Deubiquitinating Proteases Identifies Otubain-1 as a Stabilizer of c-MYC

Authors

Shannon E Moree
Laure Maneix
Polina Iakova
Fabio Stossi
Ergun Sahin
Andre Catic

Publication Date

2-4-2022

Journal

Cancers

DOI

10.3390/cancers14030806

PMID

35159073

PMCID

PMC8833929

PubMedCentral® Posted Date

2-4-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

OTUB1, c-MYC, ubiquitin–proteasome system, deubiquitinating protease, genetic screen, high-content imaging, deubiquitinase, protein turnover, oncogene, protein degradation

Abstract

The ubiquitin-proteasome pathway precisely controls the turnover of transcription factors in the nucleus, playing an important role in maintaining appropriate quantities of these regulatory proteins. The transcription factor c-MYC is essential for normal development and is a critical cancer driver. Despite being highly expressed in several tissues and malignancies, the c-MYC protein is also continuously targeted by the ubiquitin-proteasome pathway, which can either facilitate or inhibit c-MYC degradation. Deubiquitinating proteases can remove ubiquitin chains from target proteins and rescue them from proteasomal digestion. This study sought to determine novel elements of the ubiquitin-proteasome pathway that regulate c-MYC levels. We performed an overexpression screen with 41 human proteases to identify which deubiquitinases stabilize c-MYC. We discovered that the highly expressed Otubain-1 (OTUB1) protease increases c-MYC protein levels. Confirming its role in enhancing c-MYC activity, we found that elevated OTUB1 correlates with inferior clinical outcomes in the c-MYC-dependent cancer multiple myeloma, and overexpression of OTUB1 accelerates the growth of myeloma cells. In summary, our study identifies OTUB1 as a novel amplifier of the proto-oncogene c-MYC.

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