Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis

Mol Cell. 2018 Aug 16;71(4):554-566.e7. doi: 10.1016/j.molcel.2018.06.040. Epub 2018 Aug 2.

Abstract

Chromosomal rearrangements resulting in the fusion of TMPRSS2, an androgen-regulated gene, and the ETS family transcription factor ERG occur in over half of prostate cancers. However, the mechanism by which ERG promotes oncogenic gene expression and proliferation remains incompletely understood. Here, we identify a binding interaction between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which is conserved among other oncogenic ETS factors, including ETV1, ETV4, and ETV5. We find that ERG drives genome-wide retargeting of BAF complexes in a manner dependent on binding of ERG to the ETS DNA motif. Moreover, ERG requires intact BAF complexes for chromatin occupancy and BAF complex ATPase activity for target gene regulation. In a prostate organoid model, BAF complexes are required for ERG-mediated basal-to-luminal transition, a hallmark of ERG activity in prostate cancer. These observations suggest a fundamental interdependence between ETS transcription factors and BAF chromatin remodeling complexes in cancer.

Keywords: ATP-dependent chromatin remodeling; ETS transcription factors; SWI/SNF (BAF) complexes; TMPRSS2-ERG; chromatin; epigenetics; prostate cancer; transcription factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenovirus E1A Proteins / genetics
  • Adenovirus E1A Proteins / metabolism
  • Animals
  • Binding Sites
  • Carcinogenesis / genetics*
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatin / chemistry
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly
  • DNA / genetics
  • DNA / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Humans
  • Male
  • Mice, Transgenic
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Organoids / metabolism
  • Organoids / pathology
  • Prostate / metabolism
  • Prostate / pathology
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Binding
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Serine Endopeptidases / genetics*
  • Serine Endopeptidases / metabolism
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptional Regulator ERG / genetics
  • Transcriptional Regulator ERG / metabolism

Substances

  • Adenovirus E1A Proteins
  • BANF1 protein, human
  • Chromatin
  • DNA-Binding Proteins
  • ERG protein, human
  • ETV1 protein, human
  • ETV4 protein, human
  • ETV5 protein, human
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Transcriptional Regulator ERG
  • DNA
  • Serine Endopeptidases
  • TMPRSS2 protein, human