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DNA methylation by DNMT1 and DNMT3b methyltransferases is driven by the MUC1-C oncoprotein in human carcinoma cells

Oncogene volume 35, pages 6439–6445 (2016)Cite this article

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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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Abbreviations

DNMT:

DNA methyltransferase

MUC1:

mucin 1

EMT:

epithelial-mesenchymal transition

ECAD:

E-cadherin

LINE-1:

long interspersed nucleotide element-1.

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Acknowledgements

Research reported in this paper was supported by the National Cancer Institute of the National Institutes of Health under award numbers CA97098 and CA166480, and by the Lung Cancer Research Foundation.

Author contributions

HR proposed the studies, generated the promoter-reporter vectors and performed ChIP, DNA methylation ELISA and MeDIP assays. AT, MA, AB and YS performed ChIP, promoter-reporter and immunoblotting assays. SP performed bioinformatics analysis. DK designed the studies and wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Author notes

  1. Y Suzuki

    Present address: 3Current address: Department of Gastroenterological Surgery, Osaka Police Hospital, Osaka City, Osaka 543-0035, Japan.,

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    H Rajabi, A Tagde, M Alam, A Bouillez, Y Suzuki & D Kufe

  2. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA

    S Pitroda

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  1. H Rajabi
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Corresponding author

Correspondence to D Kufe.

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Competing interests

DK holds equity in Genus Oncology and is a consultant to the company. The remaining authors disclosed no potential conflicts of interest.

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Rajabi, H., Tagde, A., Alam, M. et al. DNA methylation by DNMT1 and DNMT3b methyltransferases is driven by the MUC1-C oncoprotein in human carcinoma cells. Oncogene 35, 6439–6445 (2016). https://doi.org/10.1038/onc.2016.180

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