Mucin 1 (MUC1) is a versatile oncoprotein that promotes the migration and invasion of breast cancer cells. MUC1 is up-regulated by pro-metastatic stimuli in breast cancer cells. The underlying epigenetic mechanism, however, is not fully understood. Here we report that brahma related gene 1 (BRG1), a chromatin remodeling protein, was up-regulated in highly malignant breast cancer biopsy specimens compared to those of lesser malignancy. Over-expression of BRG1 potentiated whereas depletion of BRG1 attenuated migration and invasion of MCF-7 cells. BRG1 directly bound to the MUC1 promoter and activated MUC1 transcription in a STAT1-and RelA-dependent manner. BRG1 contributed to MUC1 trans-activation by modulating histone modifications surrounding the MUC1 promoter. Specifically, BRG1 interacted with and recruited KDM3A to demethylate H3K9 on the MUC1 promoter thereby activating MUC1 transcription. Depletion of KDM3A ameliorated migration and invasion of MCF-7 cells. Altogether, our data elucidate a novel epigenetic pathway that links MUC1 transcription to breast cancer metastasis.
Keywords: BRG1; Breast cancer migration and invasion; Epigenetics; Histone demethylase; Mucin 1; Transcriptional regulation.
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