MUC1-C activates EZH2 expression and function in human cancer cells.
The EZH2 histone methyltransferase is a member of the polycomb repressive complex 2 (PRC2) that is highly expressed in diverse human cancers and is associated with a poor prognosis. MUC1-C is an oncoprotein that is similarly overexpressed in carcinomas and has been linked to epigenetic regulation. A role for MUC1-C ... in regulating EZH2 and histone methylation is not known. Here, we demonstrate that targeting MUC1-C in diverse human carcinoma cells downregulates EZH2 and other PRC2 components. MUC1-C activates (i) the EZH2 promoter through induction of the pRB→E2F pathway, and (ii) an NF-κB p65 driven enhancer in exon 1. We also show that MUC1-C binds directly to the EZH2 CXC region adjacent to the catalytic SET domain and associates with EZH2 on the CDH1 and BRCA1 promoters. In concert with these results, targeting MUC1-C downregulates EZH2 function as evidenced by (i) global and promoter-specific decreases in H3K27 trimethylation (H3K27me3), and (ii) activation of tumor suppressor genes, including BRCA1. These findings highlight a previously unreported role for MUC1-C in activating EZH2 expression and function in cancer cells.
Mesh Terms:
A549 Cells, Antigens, CD, BRCA1 Protein, Binding Sites, Cadherins, Cell Line, Tumor, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Histones, Humans, Methylation, Mucin-1, Neoplasms, Promoter Regions, Genetic, Signal Transduction, Transcriptional Activation
A549 Cells, Antigens, CD, BRCA1 Protein, Binding Sites, Cadherins, Cell Line, Tumor, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Histones, Humans, Methylation, Mucin-1, Neoplasms, Promoter Regions, Genetic, Signal Transduction, Transcriptional Activation
Sci Rep
Date: Dec. 07, 2016
PubMed ID: 28785086
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