The chromatin remodeling protein BRM regulates the transcription of tight junction proteins: Implication in breast cancer metastasis.

Claudins are a group of cell tight junction proteins that play versatile roles in cancer biology. Recent studies have correlated down-regulation of Claudins with augmented breast cancer malignancy and poor prognosis. The mechanism underlying repression of Claudin transcription in breast cancer cells is not well understood. Here we report that expression levels of Brahma (BRM) were down-regulated in triple negative breast cancer cells (MDA-231) compared to the less malignant MCF-7 cells and in high-grade human breast cancer specimens compared to low-grade ones. TGF-β treatment in MCF-7 cells repressed BRM transcription likely through targeting C/EBPβ. BRM over-expression suppressed whereas BRM knockdown promoted TGF-β induced migration and invasion of MCF-7 cells. BRM down-regulation was accompanied by the loss of a panel of Claudins in breast cancer cells. BRM directly bound to the promoter region of Claudin genes via interacting with Sp1 and activated transcription by modulating histone modifications. Together, our data have identified a novel epigenetic pathway that links Claudin transcription to breast cancer metastasis.