MUC1-C activates EZH2 expression and function in human cancer cells

作者：Rajabi Hasan; Hiraki Masayuki; Tagde Ashujit; Alam Maroof; Bouillez Audrey; Christensen Camilla L; Samur Mehmet; Wong Kwok Kin; Kufe Donald

来源：Scientific Reports, 2017, 7(1): 7481.

DOI：10.1038/s41598-017-07850-0

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>EZH2</jats:italic> 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 <jats:italic>CDH1</jats:italic> and <jats:italic>BRCA1</jats:italic> 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 <jats:italic>BRCA1</jats:italic>. These findings highlight a previously unreported role for MUC1-C in activating EZH2 expression and function in cancer cells.</jats:p>

• 出版日期2017-8-7