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Epigenetic regulation of X-linked cancer/germline antigen genes by DNMT1 and DNMT3b

Oncogene volume 25, pages 6975–6985 (2006)Cite this article

Abstract

We examined the function of two key DNA methyltransferase (DNMT) enzymes in epigenetic regulation of X-linked cancer/germline (CG-X) antigen genes in human cancer cells, using MAGE-A1, NY-ESO-1, and XAGE-1 as models. In HCT116 cells, genetic knockout of DNMT1 caused moderate activation of CG-X genes, DNMT3b knockout had a negligible effect, and double knockout of both enzymes caused robust gene induction. Similarly, dual DNMT knockout caused dramatic hypomethylation of the MAGE-A1 and NY-ESO-1 promoters, DNMT1 knockout showed moderate hypomethylation, and DNMT3b knockout elicited only slight methylation changes. In contrast, both single and double knockout cells showed significant hypomethylation of the XAGE-1 promoter. RNA interference (RNAi) targeting of DNMT1 in HCT116 cells validated the results seen using genetic knockout cells; however, RNAi targeting of DNMT1 in a different colorectal cancer cell line revealed a greater independent role for DNMT1 in mediating CG-X gene repression and promoter methylation in other cell types. Notably, the histone H3 modification pattern at CG-X promoters was altered following DNMT knockout. DNMT1 or DNMT3b knockout reduced dimethylated lysine-9 (diMe-H3K9) levels, but did not significantly affect dimethylated lysine-4 (diMe-H3K4) or acetylated lysine-9 (Ac-H3-K9) levels. In contrast, dual DNMT1/3b knockout reduced the level of diMe-H3K9 and dramatically increased the levels of diMe-H3K4 and Ac-H3K9 at CG-X gene loci. In summary, DNMT1 and DNMT3b were found to perform both redundant and independent functions in epigenetic regulation of CG-X antigen genes in human cancer cells.

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Acknowledgements

We are grateful to Dr Bert Vogelstein of The Johns Hopkins University School of Medicine for providing the DNMT knockout HCT116 cell lines, and to Dr David Jones of the University of Utah for providing the siRNA oligonucleotides targeting DNMT1. We thank other members of the Karpf laboratory, Dr Jennifer Black of RPCI, and the reviewers of this manuscript for helpful suggestions. This work was supported by grants from The Ralph Wilson Medical Research Foundation, The Roswell Park Alliance Foundation, and Phi Beta Psi (to ARK), and by NCI cancer center grant CA16056 (to Roswell Park Cancer Institute).

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  1. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Cancer Drug Center, Buffalo, New York, NY, USA

    S R James, P A Link & A R Karpf

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Correspondence to A R Karpf.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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James, S., Link, P. & Karpf, A. Epigenetic regulation of X-linked cancer/germline antigen genes by DNMT1 and DNMT3b. Oncogene 25, 6975–6985 (2006). https://doi.org/10.1038/sj.onc.1209678

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