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

Paliwal, Anupam; Vaissière, Thomas; Krais, Annette LU ; Cuenin, Cyrille; Cros, Marie-Pierre; Zaridze, David; Moukeria, Anush; Boffetta, Paolo; Hainaut, Pierre and Brennan, Paul, et al. (2010) In Cancer Research 70(7). p.88-2779
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 CHRNalpha3 gene encoding the nAChRalpha3 subunit is a frequent target of aberrant DNA hypermethylation and silencing in lung cancer, whereas the adjacent CHRNbeta4 and CHRNalpha5 genes exhibit moderate and no methylation, respectively. Treatment of cancer cells exhibiting CHRNalpha3 hypermethylation with DNA methylation inhibitors caused demethylation of the CHRNalpha3 promoter and gene reactivation. Restoring CHRNalpha3 levels through ectopic expression induced apoptotic cell death. Small hairpin RNA-mediated depletion of nAChRalpha3 in CHRNalpha3-expressing lung cancer... (More)

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 CHRNalpha3 gene encoding the nAChRalpha3 subunit is a frequent target of aberrant DNA hypermethylation and silencing in lung cancer, whereas the adjacent CHRNbeta4 and CHRNalpha5 genes exhibit moderate and no methylation, respectively. Treatment of cancer cells exhibiting CHRNalpha3 hypermethylation with DNA methylation inhibitors caused demethylation of the CHRNalpha3 promoter and gene reactivation. Restoring CHRNalpha3 levels through ectopic expression induced apoptotic cell death. Small hairpin RNA-mediated depletion of nAChRalpha3 in CHRNalpha3-expressing lung cancer cells elicited a dramatic Ca(2+) influx response in the presence of nicotine, followed by activation of the Akt survival pathway. CHRNalpha3-depleted cells were resistant to apoptosis-inducing agents, underscoring the importance of epigenetic silencing of the CHRNalpha3 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.

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@article{e91f3872-d8f0-4e61-bd45-cd52d17fac44,
  abstract     = {<p>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 CHRNalpha3 gene encoding the nAChRalpha3 subunit is a frequent target of aberrant DNA hypermethylation and silencing in lung cancer, whereas the adjacent CHRNbeta4 and CHRNalpha5 genes exhibit moderate and no methylation, respectively. Treatment of cancer cells exhibiting CHRNalpha3 hypermethylation with DNA methylation inhibitors caused demethylation of the CHRNalpha3 promoter and gene reactivation. Restoring CHRNalpha3 levels through ectopic expression induced apoptotic cell death. Small hairpin RNA-mediated depletion of nAChRalpha3 in CHRNalpha3-expressing lung cancer cells elicited a dramatic Ca(2+) influx response in the presence of nicotine, followed by activation of the Akt survival pathway. CHRNalpha3-depleted cells were resistant to apoptosis-inducing agents, underscoring the importance of epigenetic silencing of the CHRNalpha3 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.</p>},
  author       = {Paliwal, Anupam and Vaissière, Thomas and Krais, Annette and Cuenin, Cyrille and Cros, Marie-Pierre and Zaridze, David and Moukeria, Anush and Boffetta, Paolo and Hainaut, Pierre and Brennan, Paul and Herceg, Zdenko},
  issn         = {1538-7445},
  keyword      = {Apoptosis,Case-Control Studies,Cell Line, Tumor,Chromosomes, Human, Pair 15,DNA Methylation,Gene Expression Regulation, Neoplastic,Gene Knockdown Techniques,Gene Silencing,Genetic Predisposition to Disease,Humans,Lung Neoplasms,MAP Kinase Signaling System,Multigene Family,Nerve Tissue Proteins,Promoter Regions, Genetic,Receptors, Nicotinic,Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {04},
  number       = {7},
  pages        = {88--2779},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic regulation and lung cancer},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-09-4550},
  volume       = {70},
  year         = {2010},
}