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MUC1-C activates EZH2 expression and function in human cancer cells
- Source :
- Scientific Reports, Vol 7, Iss 1, Pp 1-13 (2017), Scientific Reports
- Publication Year :
- 2017
- Publisher :
- Nature Portfolio, 2017.
-
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.
- Subjects :
- Transcriptional Activation
0301 basic medicine
Science
macromolecular substances
Methylation
Article
Epigenesis, Genetic
CDH1
Histones
03 medical and health sciences
Antigens, CD
Cell Line, Tumor
Neoplasms
Histone methylation
Humans
Enhancer of Zeste Homolog 2 Protein
Epigenetics
Promoter Regions, Genetic
Enhancer
skin and connective tissue diseases
neoplasms
Regulation of gene expression
Binding Sites
Multidisciplinary
biology
BRCA1 Protein
Mucin-1
EZH2
Cadherins
digestive system diseases
biological factors
Gene Expression Regulation, Neoplastic
030104 developmental biology
A549 Cells
Histone methyltransferase
biology.protein
Cancer research
Medicine
PRC2
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 7
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....94d53cf7f2c95a86a7214ed5aef9cb28