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

Gabriel J Sandoval1, John L Pulice2, Hubert Pakula3

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Molecular Cell
|August 7, 2018
PubMed

Insights

The ETS-related gene (ERG) protein interacts with the BAF chromatin remodeling complex in prostate cancer. This interaction is crucial for ERG to control gene expression and drive cancer cell growth.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Prostate cancer frequently involves rearrangements fusing TMPRSS2 with the ETS family transcription factor ERG.
  • The precise mechanisms by which ERG drives oncogenic gene expression and proliferation are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying ERG's role in prostate cancer.
  • To identify potential interactions between ERG and cellular machinery involved in gene regulation.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) assays to assess ERG and BAF complex occupancy.
  • Prostate organoid models to study ERG function in a relevant biological context.
  • Biochemical assays to determine the dependence of ERG on BAF complex activity.

Main Results:

  • A direct binding interaction was identified between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex.
  • ERG binding to the ETS DNA motif mediates genome-wide retargeting of BAF complexes.
  • ERG requires intact BAF complexes and their ATPase activity for chromatin occupancy and target gene regulation.
  • In prostate organoids, BAF complexes are essential for ERG-driven basal-to-luminal cell transition.

Conclusions:

  • ERG and BAF chromatin remodeling complexes exhibit a fundamental interdependence in prostate cancer.
  • This interaction is conserved across other oncogenic ETS factors.
  • Targeting the ERG-BAF interaction may offer new therapeutic strategies for prostate cancer.

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