DNA methylation by DNMT1 and DNMT3b methyltransferases is driven by the MUC1-C oncoprotein in human carcinoma cells
Oncogene, 2016•nature.com
Aberrant expression of the DNA methyltransferases (DNMTs) and disruption of DNA
methylation patterns are associated with carcinogenesis and cancer cell survival. The
oncogenic MUC1-C protein is aberrantly overexpressed in diverse carcinomas; however,
there is no known link between MUC1-C and DNA methylation. Our results demonstrate that
MUC1-C induces the expression of DNMT1 and DNMT3b, but not DNMT3a, in breast and
other carcinoma cell types. We show that MUC1-C occupies the DNMT1 and DNMT3b …
methylation patterns are associated with carcinogenesis and cancer cell survival. The
oncogenic MUC1-C protein is aberrantly overexpressed in diverse carcinomas; however,
there is no known link between MUC1-C and DNA methylation. Our results demonstrate that
MUC1-C induces the expression of DNMT1 and DNMT3b, but not DNMT3a, in breast and
other carcinoma cell types. We show that MUC1-C occupies the DNMT1 and DNMT3b …
Abstract
Aberrant expression of the DNA methyltransferases (DNMTs) and disruption of DNA methylation patterns are associated with carcinogenesis and cancer cell survival. The oncogenic MUC1-C protein is aberrantly overexpressed in diverse carcinomas; however, there is no known link between MUC1-C and DNA methylation. Our results demonstrate that MUC1-C induces the expression of DNMT1 and DNMT3b, but not DNMT3a, in breast and other carcinoma cell types. We show that MUC1-C occupies the DNMT1 and DNMT3b promoters in complexes with NF-κB p65 and drives DNMT1 and DNMT3b transcription. In this way, MUC1-C controls global DNA methylation as determined by analysis of LINE-1 repeat elements. The results further demonstrate that targeting MUC1-C downregulates DNA methylation of the CDH1 tumor suppressor gene in association with induction of E-cadherin expression. These findings provide compelling evidence that MUC1-C is of functional importance to induction of DNMT1 and DNMT3b and, in turn, changes in DNA methylation patterns in cancer cells.
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