Rajabi, HasanHiraki, MasayukiTagde, AshujitAlam, MaroofBouillez, AudreyChristensen, CamillaSamur, MehmetWong, Kwok-KinKufe, Donald2017-11-212017Rajabi, Hasan, Masayuki Hiraki, Ashujit Tagde, Maroof Alam, Audrey Bouillez, Camilla L. Christensen, Mehmet Samur, Kwok-Kin Wong, and Donald Kufe. 2017. “MUC1-C activates EZH2 expression and function in human cancer cells.” Scientific Reports 7 (1): 7481. doi:10.1038/s41598-017-07850-0. http://dx.doi.org/10.1038/s41598-017-07850-0.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34375271The 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.en-USJournal Article2017-11-2110.1038/s41598-017-07850-0