DNMT1 and DNMT3b cooperate to silence genes in human cancer cells

Ina Rhee, Kurtis E. Bachman, Ben Ho Park, Kam-Wing Jair, Ray-Whay Chiu Yen, Kornel E. Schuebel, Hengmi Cui, Andrew P. Feinberg, Christoph Lengauer, Kenneth W. Kinzler, Stephen B. Baylin () and Bert Vogelstein ()
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Ina Rhee: Johns Hopkins University School of Medicine
Kurtis E. Bachman: Johns Hopkins University School of Medicine
Ben Ho Park: Johns Hopkins University School of Medicine
Kam-Wing Jair: Johns Hopkins University School of Medicine
Ray-Whay Chiu Yen: Johns Hopkins University School of Medicine
Kornel E. Schuebel: Johns Hopkins University School of Medicine
Hengmi Cui: Johns Hopkins University School of Medicine
Andrew P. Feinberg: Johns Hopkins University School of Medicine
Christoph Lengauer: Johns Hopkins University School of Medicine
Kenneth W. Kinzler: Johns Hopkins University School of Medicine
Stephen B. Baylin: Johns Hopkins University School of Medicine
Bert Vogelstein: Johns Hopkins University School of Medicine

Nature, 2002, vol. 416, issue 6880, 552-556

Abstract: Abstract Inactivation of tumour suppressor genes is central to the development of all common forms of human cancer1. This inactivation often results from epigenetic silencing associated with hypermethylation rather than intragenic mutations2,3,4,5,6,7. In human cells, the mechanisms underlying locus-specific or global methylation patterns remain unclear8,9. The prototypic DNA methyltransferase, Dnmt1, accounts for most methylation in mouse cells10,11, but human cancer cells lacking DNMT1 retain significant genomic methylation and associated gene silencing12. We disrupted the human DNMT3b gene in a colorectal cancer cell line. This deletion reduced global DNA methylation by less than 3%. Surprisingly, however, genetic disruption of both DNMT1 and DNMT3b nearly eliminated methyltransferase activity, and reduced genomic DNA methylation by greater than 95%. These marked changes resulted in demethylation of repeated sequences, loss of insulin-like growth factor II (IGF2) imprinting, abrogation of silencing of the tumour suppressor gene p16INK4a, and growth suppression. Here we demonstrate that two enzymes cooperatively maintain DNA methylation and gene silencing in human cancer cells, and provide compelling evidence that such methylation is essential for optimal neoplastic proliferation.

Date: 2002
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DOI: 10.1038/416552a

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