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

Alexandra M. Blee, Shujun Liu, Liguo Wang, Haojie Huang

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Prostate cancer (PCa) that becomes resistant to hormone castration and nextgeneration 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 acetylationmimicking 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.

Original languageEnglish (US)
Pages (from-to)38319-38332
Number of pages14
JournalOncotarget
Volume7
Issue number25
DOIs
StatePublished - 2016

Keywords

  • Acetylation
  • BRD4
  • Bromodomain
  • Cell invasion
  • ERG

ASJC Scopus subject areas

  • Oncology

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