Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers.

Proc Natl Acad Sci U S A
Authors
Abstract

The use of proteasome inhibitors to target cancer's dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic proteasome inhibitor resistance. Moreover, such proteasome subunit suppression is associated with poor outcome in myeloma patients, where proteasome inhibitors are a mainstay of treatment. Beyond conferring resistance to proteasome inhibitors, proteasome subunit suppression also serves as a sentinel of a more global remodeling of the transcriptome. This remodeling produces a distinct gene signature and new vulnerabilities to the proapoptotic drug, ABT-263. This frequent, naturally arising imbalance in 19S regulatory complex composition is achieved through a variety of mechanisms, including DNA methylation, and marks the emergence of a heritably altered and therapeutically relevant state in diverse cancers.

Year of Publication
2017
Journal
Proc Natl Acad Sci U S A
Volume
114
Issue
2
Pages
382-387
Date Published
2017 Jan 10
ISSN
1091-6490
DOI
10.1073/pnas.1619067114
PubMed ID
28028240
PubMed Central ID
PMC5240730
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