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

Citation:

Gabriel J Sandoval, John L Pulice, Hubert Pakula, Monica Schenone, David Y Takeda, Marius Pop, Gaylor Boulay, Kaylyn E Williamson, Matthew J McBride, Joshua Pan, Roodolph St Pierre, Emily Hartman, Levi A Garraway, Steven A Carr, Miguel N Rivera, Zhe Li, Lucienne Ronco, William C Hahn, and Cigall Kadoch. 2018. “Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis.” Mol Cell, 71, 4, Pp. 554-566.e7.

Abstract:

Chromosomal rearrangements resulting in the fusion of TMPRSS2, an androgen-regulated gene, and the ETS family transcription factor ERG occur in over half of prostate cancers. However, the mechanism by which ERG promotes oncogenic gene expression and proliferation remains incompletely understood. Here, we identify a binding interaction between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which is conserved among other oncogenic ETS factors, including ETV1, ETV4, and ETV5. We find that ERG drives genome-wide retargeting of BAF complexes in a manner dependent on binding of ERG to the ETS DNA motif. Moreover, ERG requires intact BAF complexes for chromatin occupancy and BAF complex ATPase activity for target gene regulation. In a prostate organoid model, BAF complexes are required for ERG-mediated basal-to-luminal transition, a hallmark of ERG activity in prostate cancer. These observations suggest a fundamental interdependence between ETS transcription factors and BAF chromatin remodeling complexes in cancer.