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

Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):382-387. doi: 10.1073/pnas.1619067114. Epub 2016 Dec 27.

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.

Keywords: EMT; apoptosis; bortezomib; drug resistance; epigenetic gene regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • DNA Methylation / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism*
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / pharmacology*

Substances

  • Proteasome Inhibitors
  • Proteasome Endopeptidase Complex