Smoking-induced lung tumors exhibit characteristic changes in gene expression, e.g. silencing of tumor suppressor genes and DNA repair genes by hypermethylation of CG-rich promoter regions and activation of oncogenes by promoter hypomethylation.  It has been proposed that epigenetic modification is an important mechanism of gene activation and inactivation in cancer. 5-Methylcytosine (MeC) is an important regulator of gene expression that is formed by enzymatic methylation of the C5 position of cytosine in CG dinucleotides (CpG sites). In addition to  MeC, recent studies have discovered several related epigenetic modifications, including 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). These minor nucleobases are thought to arise from TET (ten eleven translocation protein)-mediated oxidation of the methyl group of MeC. In the present work, we employed sensitive and specific HPLC-ESI-MS/MS methodology to quantify MeC, 5hmC, 5fC, and 5caC in human bronchial epithelial cells treated with metabolically activated NNK and in tissues of laboratory mice chronically treated with NNK by gavage. We found that while MeC levels in tissues remained unchanged, 5hmC concentrations decreased upon chronic administration of NNK. An even greater change was observed in animals co-administered with lipopolysaccharide to induce inflammation. Our results suggest that NNK-induced epigenetic changes may contribute to tobacco-mediated carcinogenesis.

Epigenetic changes in cells and animals treated with tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

246th National Meeting (2013)

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