Aberrant DNA Methylation Links Cancer Susceptibility Locus 15q25.1 to Apoptotic Regulation and Lung Cancer

Abstract

Nicotinic acetylcholine receptor (nAChR) genes form a highly conserved gene cluster at the lung cancer susceptibility locus 15q25.1. In this study, we show that the CHRNα3 gene encoding the nAChRα3 subunit is a frequent target of aberrant DNA hypermethylation and silencing in lung cancer, whereas the adjacent CHRNβ4 and CHRNα5 genes exhibit moderate and no methylation, respectively. Treatment of cancer cells exhibiting CHRNα3 hypermethylation with DNA methylation inhibitors caused demethylation of the CHRNα3 promoter and gene reactivation. Restoring CHRNα3 levels through ectopic expression induced apoptotic cell death. Small hairpin RNA-mediated depletion of nAChRα3 in CHRNα3-expressing lung cancer cells elicited a dramatic Ca 2+ influx response in the presence of nicotine, followed by activation of the Akt survival pathway.CHRNα3-depleted cells were resistant to apoptosis-inducing agents, underscoring the importance of epigenetic silencing of the CHRNα3 gene in human cancer. In defining a mechanism of epigenetic control of nAChR expression in nonneuronal tissues, our findings offer a functional link between susceptibility locus 15q25.1 and lung cancer, and suggest nAChRs to be theranostic targets for cancer detection and chemoprevention. CancerRes; 70(7); 2779-88. ©2010 AACR.

Epigenetic regulation of DNA methyltransferases: DNMT1 and DNMT3B in gliomas

“…Genetic disruption of both DNMT1 and DNMT3B was shown to eliminate methyltransferase activity and thereby reduce DNA methylation by greater than 95% [31]. Abnormal methylation of DNA and repressive histone modifications contribute to epigenetic silencing of TSGs in multistage human carcinogenesis [32][33][34][35]. Overexpression of DNMTs is found in several cancers, including hepatocellular, breast, pancreatic, and cervical cancers [36][37][38].…”

DNA methylation changes associated with risk factors in tumors of the upper aerodigestive tract

“…This suggests that hypermethylation of the CHRNA3 gene, a member of the family of genes encoding subunits of nicotinic acetylcholine receptors (nAChRs) clustered at lung cancer susceptibility locus 15q25, 25 that is frequently silenced in lung cancer, 26 may also be involved in be epigenetic deregulation of nAChR receptors in UADT tumors. Similarly, our study identifies the frequent hypermethylation of MTHFR, the gene encoding the enzyme known to play a critical role in maintaining an adequate methionine pool, 27 in UADT tumors.…”

Dietary supplementation with polyunsaturated fatty acid during pregnancy modulates DNA methylation at IGF2/H19 imprinted genes and growth of infants

“…DNA methylation analysis was performed by pyrosequencing after DNA extraction from CBMCs and bisulfite conversion as previously described (33). We established pyrosequencing assays for quantitative measurement of DNA methylation levels in the promoter region of target genes in the DHA-supplemented and the control groups: IGF2 P3, IGF2 DMR, and H19 DMR.…”