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

作者：Paliwal Anupam; Vaissiere Thomas; Krais Annette; Cuenin Cyrille; Cros Marie Pierre; Zaridze David; Moukeria Anush; Boffetta Paolo; Hainaut Pierre; Brennan Paul; Herceg Zdenko^*

来源：Cancer Research, 2010, 70(7): 2779-2788.

DOI：10.1158/0008-5472.CAN-09-4550

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 CHRN alpha 3 gene encoding the nAChRa3 subunit is a frequent target of aberrant DNA hypermethylation and silencing in lung cancer, whereas the adjacent CHRN beta 4 and CHRN alpha 5 genes exhibit moderate and no methylation, respectively. Treatment of cancer cells exhibiting CHRN alpha 3 hypermethylation with DNA methylation inhibitors caused demethylation of the CHRN alpha 3 promoter and gene reactivation. Restoring CHRN alpha 3 levels through ectopic expression induced apoptotic cell death. Small hairpin RNA-mediated depletion of nAChRa3 in CHRN alpha 3-expressing lung cancer cells elicited a dramatic Ca(2+) influx response in the presence of nicotine, followed by activation of the Akt survival pathway. CHRN alpha 3-depleted cells were resistant to apoptosis-inducing agents, underscoring the importance of epigenetic silencing of the CHRN alpha 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. Cancer Res; 70(7); 2779-88.

• 出版日期2010-4-1