In TMPRSS2–ERG-positive prostate cancer, ERG retargets BAF chromatin remodeling complexes to ETS motifs.

  • Major finding: In TMPRSS2–ERG-positive prostate cancer, ERG retargets BAF chromatin remodeling complexes to ETS motifs.

  • Concept: BAF complexes are required for ERG target gene expression and ERG-mediated basal to luminal transition.

  • Impact: Targeting the ERG–BAF interaction may potentially disrupt oncogenesis in TMPRSS2–ERG-positive tumors.

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Chromosomal translocations resulting in the TMPRSS2–ERG gene fusion occur in the majority of prostate cancers and result in the upregulation of the ETS family transcription factor ERG. However, the mechanisms by which ERG drives prostate tumorigenesis are not fully understood. To understand how ERG drives oncogenic gene expression, Sandoval, Pulice, and colleagues performed immunoprecipitation followed by stable isotope labeling with amino acids in cell culture (SILAC)–based proteomic mass spectrometry to identify proteins that bind to ERG. This approach revealed that ERG interacts with multiple components of the BAF (also known as SWI/SNF) chromatin remodeling complex. In addition, other ETS family transcription factors, including ETV1, ETV4, and ETV5, which are also overexpressed in a subset of prostate cancers, also interacted with BAF complexes. Depletion of BAF subunits reduced the viability of prostate cancer cells. Chromatin immunoprecipitation sequencing found that ERG promotes genome-wide retargeting of BAF complexes to ETS DNA motifs to regulate target gene expression. ERG chromatin occupancy required intact BAF complexes, and BAF ATPase activity was required for regulation of ERG target genes. In prostate cancer organoids, ERG promoted the basal to luminal transition characteristic of prostate oncogenesis, and this process could be suppressed by reducing levels of the BAF complex protein BRG, resulting in an increase in basal morphology and a reduction in luminal morphology. Collectively, these findings indicate that ERG recruits BAF complexes to ETS motifs, thereby promoting expression of ERG target genes to drive prostate tumorigenesis, and suggest the potential for therapeutic targeting of the ERG–BAF interaction in prostate cancer.

Sandoval GJ, Pulice JL, Pakula H, Schenone M, Takeda DY, Pop M, et al. Binding of TMPRSS2-ERG to BAF chromatin remodeling complexes mediates prostate oncogenesis. Mol Cell 2018 Aug 2 [Epub ahead of print].

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©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.