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

Abstract 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 regu...

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Autores principales:	Hasan Rajabi, Masayuki Hiraki, Ashujit Tagde, Maroof Alam, Audrey Bouillez, Camilla L. Christensen, Mehmet Samur, Kwok-Kin Wong, Donald Kufe
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/56075f33571249bb9a4c88495e6d72f5
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spelling	oai:doaj.org-article:56075f33571249bb9a4c88495e6d72f52021-12-02T11:40:12ZMUC1-C activates EZH2 expression and function in human cancer cells10.1038/s41598-017-07850-02045-2322https://doaj.org/article/56075f33571249bb9a4c88495e6d72f52017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07850-0https://doaj.org/toc/2045-2322Abstract 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.Hasan RajabiMasayuki HirakiAshujit TagdeMaroof AlamAudrey BouillezCamilla L. ChristensenMehmet SamurKwok-Kin WongDonald KufeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hasan Rajabi Masayuki Hiraki Ashujit Tagde Maroof Alam Audrey Bouillez Camilla L. Christensen Mehmet Samur Kwok-Kin Wong Donald Kufe MUC1-C activates EZH2 expression and function in human cancer cells
description	Abstract 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.
format	article
author	Hasan Rajabi Masayuki Hiraki Ashujit Tagde Maroof Alam Audrey Bouillez Camilla L. Christensen Mehmet Samur Kwok-Kin Wong Donald Kufe
author_facet	Hasan Rajabi Masayuki Hiraki Ashujit Tagde Maroof Alam Audrey Bouillez Camilla L. Christensen Mehmet Samur Kwok-Kin Wong Donald Kufe
author_sort	Hasan Rajabi
title	MUC1-C activates EZH2 expression and function in human cancer cells
title_short	MUC1-C activates EZH2 expression and function in human cancer cells
title_full	MUC1-C activates EZH2 expression and function in human cancer cells
title_fullStr	MUC1-C activates EZH2 expression and function in human cancer cells
title_full_unstemmed	MUC1-C activates EZH2 expression and function in human cancer cells
title_sort	muc1-c activates ezh2 expression and function in human cancer cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/56075f33571249bb9a4c88495e6d72f5
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MUC1-C activates EZH2 expression and function in human cancer cells

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