BRG1 promotes transcriptional patterns that are permissive to proliferation in cancer cells

Abstract

ABSTRACTBackgroundBRG1 (encoded bySMARCA4) is a catalytic component of the SWI/SNF chromatin remodelling complex, with key roles in modulating DNA accessibility. Dysregulation of BRG1 is observed, but functionally uncharacterised, in a wide range of malignancies. We have probed the functions of BRG1 on a background of prostate cancer to investigate how BRG1 controls gene expression programs and cancer cell behaviour.ResultsOur investigation ofSMARCA4revealed that BRG1 is universally overexpressed in 486 tumours from The Cancer Genome Atlas prostate cohort, as well as in a complementary panel of 21 prostate cell lines. Next, we utilised a temporal model of BRG1 depletion to investigate the molecular effects on global transcription programs. Unexpectedly, depleting BRG1 had no impact on alternative splicing and conferred only modest effect on global expression. However, of the transcriptional changes that occurred, most manifested as down-regulated expression. Deeper examination found the common thread linking down-regulated genes was involvement in proliferation, including several known to increase prostate cancer proliferation (KLK2,PCAT1andVAV3). Interestingly, the promoters of genes driving proliferation were bound by BRG1 as well as the oncogenic transcription factors, AR and FOXA1. We also noted that BRG1 depletion repressed genes involved in cell cycle progression and DNA replication but intriguingly, these pathways operated independently of AR and FOXA1. In agreement with transcriptional changes, depleting BRG1 conferred G1 arrest.ConclusionsOur data have revealed that BRG1 has capacity to drive oncogenesis by coordinating oncogenic pathways dependent on BRG1 for proliferation, cell cycle progression and DNA replication.