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

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.

Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

“…Through interaction with lineage-regulating factors, SWI/SNF may be re-targeted to specific sites of the genome and participate in maintaining an adenocarcinoma phenotype or in neuroendocrine progression. This working hypothesis could be in line by recent findings in a subset of PCa that harbor the TMPRSS2:ERG gene fusion, where ERG binding to SWI/SNF has been shown to drive genome-wide retargeting of SWI/SNF complexes and activation of specific gene expression programs 72 .…”

“…From the functional perspective, inhibition of the SWI/SNF subunits BAF57 (SMARCE1) or BAF53A (ACTL6A) in PCa cells has shown to abrogate androgen-dependent cell proliferation 70,71 . Similarly, Sandoval et al reported that SWI/SNF interacts with ERG in PCa cells harboring the TMPRSS2:ERG gene fusion and is required to activate specific gene programs and maintain cell growth 72 . Although on the contrary, Prensner et al had suggested that SWI/SNF acts as a tumor suppressor in PCa, by demonstrating an antagonistic relationship between the pro-oncogenic long non-coding RNA SChLAP1 and the SWI/SNF core subunit BAF47 73 , a subsequent study failed to confirm that SChLAP1-SWI/SNF interaction leads to depletion of SWI/SNF from the genome 74 .…”

BRG1 is a prognostic indicator and a potential therapeutic target for prostate cancer

“…In addition, BRG1 is required for various aspects of cancer cell survival, proliferation, and function in HeLa cells (64), leukemia cells (65,66), breast cancer (33,43), hepatocarcinoma (67), colorectal cancer (68), neuroblastoma (29), melanoma (30,69,70), and certain medullablastoma tumors (71). Recent evidence indicates that the fusion between the TMPRSS2 gene and the ETS family transcription factor, ERG, that occurs in half of prostate cancers, mediates its oncogenic effect at least in part by interacting with the human SWI/SNF enzymes and re-directing its chromatin interactions across the genome (72). Thus the chromatin remodeling enzyme and presumably its enzymatic function is a required component contributing to prostate oncogenesis.…”

MUC1-C Activates the NuRD Complex to Drive Dedifferentiation of Triple-Negative Breast Cancer Cells

“…Total and nuclear lysates prepared from subconfluent cells were subjected to immunoblot analysis using anti-MUC1-C (#HM-1630-P1ABX; Thermo Fisher Scientific), anti-MYC (#ab32072; Abcam), anti-ERa (#ab108398; Abcam), anti-b-actin (#A5441; Sigma), anti-MTA1 (#5647), anti-MBD3 (#14540), anti-CHD4 (#11912), anti-HDAC1 (#5356), anti-SOX2 (#D6D9), anti-KLF4 (#D1F2), anti-BMI1 (#D20B7), anti-CD44 (#156-3C11), and anti-OCT4 (#2750S; Cell Signaling Technology). Nuclear proteins were immunoprecipitated in the absence and presence of 50 mg/mL ethidium bromide (EtBr; #15585-011, Thermo Fisher Scientific) as described (25).…”