Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms

Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66. doi: 10.1073/pnas.1608319113. Epub 2016 Jul 18.

Abstract

Bromodomain and extraterminal domain protein inhibitors (BETi) hold great promise as a novel class of cancer therapeutics. Because acquired resistance typically limits durable responses to targeted therapies, it is important to understand mechanisms by which tumor cells adapt to BETi. Here, through pooled shRNA screening of colorectal cancer cells, we identified tripartite motif-containing protein 33 (TRIM33) as a factor promoting sensitivity to BETi. We demonstrate that loss of TRIM33 reprograms cancer cells to a more resistant state through at least two mechanisms. TRIM33 silencing attenuates down-regulation of MYC in response to BETi. Moreover, loss of TRIM33 enhances TGF-β receptor expression and signaling, and blocking TGF-β receptor activity potentiates the antiproliferative effect of BETi. These results describe a mechanism for BETi resistance and suggest that combining inhibition of TGF-β signaling with BET bromodomain inhibition may offer new therapeutic benefits.

Keywords: JQ1; TGF-β; TRIM33; bromodomain inhibitor; drug resistance.

MeSH terms

  • Azepines / chemistry
  • Azepines / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Drug Resistance / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA Interference
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • (+)-JQ1 compound
  • Azepines
  • Proteins
  • Proto-Oncogene Proteins c-myc
  • Receptors, Transforming Growth Factor beta
  • TRIM33 protein, human
  • Transcription Factors
  • Transforming Growth Factor beta
  • Triazoles
  • bromodomain and extra-terminal domain protein, human