BET bromodomain-mediated interaction between ERG and BRD4 promotes prostate cancer cell invasion

Oncotarget. 2016 Jun 21;7(25):38319-38332. doi: 10.18632/oncotarget.9513.


Prostate cancer (PCa) that becomes resistant to hormone castration and next-generation androgen receptor (AR)-targeted therapies, called castration-resistant prostate cancer (CRPC), poses a significant clinical challenge. A better understanding of PCa progression and key molecular mechanisms could bring novel therapies to light. One potential therapeutic target is ERG, a transcription factor aberrantly up-regulated in PCa due to chromosomal rearrangements between androgen-regulated gene TMPRSS2 and ERG. Here we show that the most common PCa-associated truncated ERG T1-E4 (ERGΔ39), encoded by fusion between TMPRSS2 exon 1 and ERG exon 4, binds to bromodomain-1 (BD1) of bromodomain containing protein 4 (BRD4), a member of the bromodomain and extraterminal domain (BET) family. This interaction is partially abrogated by BET inhibitors JQ1 and iBET762. Meta-analysis of published ERG (T1-E4) and BRD4 chromatin immunoprecipitation-sequencing (ChIP-seq) data demonstrates overlap in a substantial portion of their binding sites. Gene expression profile analysis shows some ERG-BRD4 co-target genes are upregulated in CRPC compared to hormone-naïve counterparts. We provide further evidence that ERG-mediated invasion of PCa cells was significantly enhanced by an acetylation-mimicking mutation in ERG that augments the ERG-BRD4 interaction. Our findings reveal that PCa-associated ERG can interact and co-occupy with BRD4 in the genome, and suggest this druggable interaction is critical for ERG-mediated cell invasion and PCa progression.

Keywords: BRD4; ERG; acetylation; bromodomain; cell invasion.

MeSH terms

  • Azepines / pharmacology
  • Base Sequence
  • Benzodiazepines / pharmacology
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • HEK293 Cells
  • Humans
  • Male
  • Neoplasm Invasiveness
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Proteins / antagonists & inhibitors
  • Proteins / genetics
  • Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Regulator ERG / genetics
  • Transcriptional Regulator ERG / metabolism
  • Triazoles / pharmacology


  • (+)-JQ1 compound
  • Azepines
  • BRD4 protein, human
  • Cell Cycle Proteins
  • ERG protein, human
  • Nuclear Proteins
  • Proteins
  • Transcription Factors
  • Transcriptional Regulator ERG
  • Triazoles
  • bromodomain and extra-terminal domain protein, human
  • Benzodiazepines
  • molibresib