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 CHRNa3 gene encoding the nAChRa3 subunit is a frequent target of aberrant DNA hypermethylation and silencing in lung cancer, whereas the adjacent CHRNß4 and CHRNa5 genes exhibit moderate and no methylation, respectively. Treatment of cancer cells exhibiting CHRNa3 hypermethylation with DNA methylation inhibitors caused demethylation of the CHRNa3 promoter and gene reactivation. Restoring CHRNa3 levels through ectopic expression induced apoptotic cell death. Small hairpin RNA-mediated depletion of nAChRalpha;3 in CHRNalpha;3-expressing lung cancer cells elicited a dramatic Ca2+ influx response in the presence of nicotine, followed by activation of the Akt survival pathway. CHRNalpha;3-depleted cells were resistant to apoptosis-inducing agents, underscoring the importance of epigenetic silencing of the CHRNalpha;3 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. ©2010 American Association for Cancer Research.

Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic regulation and lung cancer

Boffetta, P.;
2010

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 CHRNa3 gene encoding the nAChRa3 subunit is a frequent target of aberrant DNA hypermethylation and silencing in lung cancer, whereas the adjacent CHRNß4 and CHRNa5 genes exhibit moderate and no methylation, respectively. Treatment of cancer cells exhibiting CHRNa3 hypermethylation with DNA methylation inhibitors caused demethylation of the CHRNa3 promoter and gene reactivation. Restoring CHRNa3 levels through ectopic expression induced apoptotic cell death. Small hairpin RNA-mediated depletion of nAChRalpha;3 in CHRNalpha;3-expressing lung cancer cells elicited a dramatic Ca2+ influx response in the presence of nicotine, followed by activation of the Akt survival pathway. CHRNalpha;3-depleted cells were resistant to apoptosis-inducing agents, underscoring the importance of epigenetic silencing of the CHRNalpha;3 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. ©2010 American Association for Cancer Research.
2010
Paliwal, A.; Vaissière, T.; Krais, A.; Cuenin, C.; Cros, M.-P.; Zaridze, D.; Moukeria, A.; Boffetta, P.; Hainaut, P.; Brennan, P.; Herceg, Z.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/682750
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