The chromatin remodeling protein BRG1 links ELOVL3 trans-activation to prostate cancer metastasis

Abstract

Prostate cancer malignancies are intimately correlated with deregulated fatty acid metabolism. The underlying epigenetic mechanism is not fully understood. In the present study we investigated the mechanism whereby the chromatin remodeling protein BRG1 regulates the transcription of long-chain fatty acid elongase 3 (Elovl3) in prostate cancer cells. We report that in response to pro-metastatic cues (androgen and TGF-β) BRG1 expression was up-regulated along with Elvol3 in prostate cancer cells. BRG1 over-expression potentiated whereas BRG1 knockdown attenuated prostate cancer cell migration and invasion. Coincidently, Elovl3 was up-regulated following BRG1 over-expression and down-regulated after BRG1 knockdown in prostate cancer cells. Further analysis revealed that BRG1 interacted with and was recruited by retinoic acid receptor-related orphan receptor (RORγ) to the Elovl3 promoter to activate transcription. Chromatin immunoprecipitation (ChIP) profiling demonstrated that BRG1 interacted with histone acetyltransferase p300 to activate Elovl3 transcription. Depletion of p300 by siRNA or inhibition of p300 by curcumin attenuated Elovl3 trans-activation in prostate cancer cells. Together, our data identify a novel epigenetic pathway that links Elovl3 transcription to prostate cancer cell migration and invasion.