Cytosine-DNA Methyltransferase Mediates Carcinogen-Induced Gene Promoter Methylation

Steven A. Belinsky, Ph.D.
Lung Cancer Program, Lovelace Respiratory Research Institute
NIEHS Grant R01ES008801

NIEHS-supported researchers studying the basic cellular and molecular events that occur after exposure to carcinogens report differences in DNA repair capacity in bronchial epithelial cell lines after low-dose treatment with methyl-nitrosourea and benzo(a)pyrene-diolepoxide. They also found that levels of cytosine-DNA methyltransferase 1 (DNMT1) increased significantly during the carcinogen exposure and were linked to promoter-hypermethylation of several genes in each transformed cell line. These finding may have implications for preventing lung cancer in smokers.

When the researchers employed strategies to reduce the production of the DNMT1 protein, cell transformation and gene silencing were reversed. Reduced DNMT1 production prior to carcinogen exposure prevented transformation and gene methylation.

These studies and findings describe a mechanistic link between increased DNMT1, methylation of tumor suppressor genes and reduced DNA repair capacity that together appear to cause cancer-like changes in lung epithelial cells. The study also provides evidence for the use of demethylation strategies to prevent lung cancer in smokers.

Citation: Damiani LA, Yingling CM, Leng S, Romo PE, Nakamura J, Belinsky SA. Carcinogen-induced gene promoter hypermethylation is mediated by DNMT1 and causal for transformation of immortalized bronchial epithelial cells. Cancer Res. 2008 Nov 1;68(21):9005-14.