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

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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; Cuenin, Cyrille; Cros, Marie-Pierre; Zaridze, David; Moukeria, Anush; Boffetta, Paolo; Hainaut, Pierre; Brennan, Paul; Herceg, Zdenko.

I: Cancer Research, Vol. 70, Nr. 7, 01.04.2010, s. 2779-88.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Paliwal, A, Vaissière, T, Krais, A, Cuenin, C, Cros, M-P, Zaridze, D, Moukeria, A, Boffetta, P, Hainaut, P, Brennan, P & Herceg, Z 2010, 'Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic regulation and lung cancer', Cancer Research, vol. 70, nr. 7, s. 2779-88. https://doi.org/10.1158/0008-5472.CAN-09-4550

APA

CBE

Paliwal A, Vaissière T, Krais A, Cuenin C, Cros M-P, Zaridze D, Moukeria A, Boffetta P, Hainaut P, Brennan P, Herceg Z. 2010. Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic regulation and lung cancer. Cancer Research. 70(7):2779-88. https://doi.org/10.1158/0008-5472.CAN-09-4550

MLA

Vancouver

Author

Paliwal, Anupam ; Vaissière, Thomas ; Krais, Annette ; Cuenin, Cyrille ; Cros, Marie-Pierre ; Zaridze, David ; Moukeria, Anush ; Boffetta, Paolo ; Hainaut, Pierre ; Brennan, Paul ; Herceg, Zdenko. / Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic regulation and lung cancer. I: Cancer Research. 2010 ; Vol. 70, Nr. 7. s. 2779-88.

RIS

TY - JOUR

T1 - Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic regulation and lung cancer

AU - Paliwal, Anupam

AU - Vaissière, Thomas

AU - Krais, Annette

AU - Cuenin, Cyrille

AU - Cros, Marie-Pierre

AU - Zaridze, David

AU - Moukeria, Anush

AU - Boffetta, Paolo

AU - Hainaut, Pierre

AU - Brennan, Paul

AU - Herceg, Zdenko

PY - 2010/4/1

Y1 - 2010/4/1

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Case-Control Studies

KW - Cell Line, Tumor

KW - Chromosomes, Human, Pair 15

KW - DNA Methylation

KW - Gene Expression Regulation, Neoplastic

KW - Gene Knockdown Techniques

KW - Gene Silencing

KW - Genetic Predisposition to Disease

KW - Humans

KW - Lung Neoplasms

KW - MAP Kinase Signaling System

KW - Multigene Family

KW - Nerve Tissue Proteins

KW - Promoter Regions, Genetic

KW - Receptors, Nicotinic

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1158/0008-5472.CAN-09-4550

DO - 10.1158/0008-5472.CAN-09-4550

M3 - Article

VL - 70

SP - 2779

EP - 2788

JO - Cancer research. Supplement

T2 - Cancer research. Supplement

JF - Cancer research. Supplement

SN - 1538-7445

IS - 7

ER -