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

Alexandra M Blee1,2, Shujun Liu3, Liguo Wang4

  • 1Mayo Graduate School, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, 55905, USA.

Oncotarget
|May 26, 2016
PubMed

Insights

Prostate cancer progression involves ERG and BRD4 interaction. Targeting this ERG-BRD4 binding offers a new therapeutic strategy for castration-resistant prostate cancer (CRPC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Castration-resistant prostate cancer (CRPC) is a major clinical challenge.
  • Understanding prostate cancer (PCa) progression mechanisms is crucial for novel therapies.
  • ERG is a transcription factor often overexpressed in PCa due to gene fusions.

Purpose of the Study:

  • To investigate the interaction between ERG and BRD4 in prostate cancer.
  • To explore the functional significance of the ERG-BRD4 interaction in PCa progression.

Main Methods:

  • Analyzing the binding of ERG T1-E4 to BRD4 BD1.
  • Using BET inhibitors (JQ1, iBET762) to study the interaction.
  • Performing meta-analysis of ChIP-seq data for ERG and BRD4.
  • Analyzing gene expression profiles.
  • Utilizing mutation analysis to assess ERG-BRD4 interaction effects.

Main Results:

  • ERG T1-E4 directly binds to BRD4 BD1.
  • BET inhibitors partially disrupt the ERG-BRD4 interaction.
  • ERG and BRD4 share significant genomic binding sites.
  • ERG-BRD4 co-target genes are upregulated in CRPC.
  • An acetylation-mimicking mutation in ERG enhances ERG-BRD4 interaction and PCa cell invasion.

Conclusions:

  • ERG interacts with and co-occupies genomic sites with BRD4 in PCa.
  • The ERG-BRD4 interaction is critical for ERG-mediated cell invasion.
  • This druggable interaction represents a potential therapeutic target for PCa progression.

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