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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Anupam Paliwal
  • Thomas Vaissière
  • Annette Krais
  • Cyrille Cuenin
  • Marie-Pierre Cros
  • David Zaridze
  • Anush Moukeria
  • Paolo Boffetta
  • Pierre Hainaut
  • Paul Brennan
  • Zdenko Herceg
External organisations
  • International Agency for Research on Cancer, World Health Organization
Research areas and keywords

Keywords

  • 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
Original languageEnglish
Pages (from-to)2779-88
Number of pages10
JournalCancer Research
Volume70
Issue number7
Publication statusPublished - 2010 Apr 1
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes