Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic regulation and lung cancer.
Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic regulation and lung cancer.
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DOI：
10.1158/0008-5472.can-09-4550
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发表时间：
2010-04-01
期刊：
影响因子：
11.2
通讯作者：
Herceg Z
中科院分区：
文献类型：
--
作者：
Paliwal A;Vaissière T;Krais A;Cuenin C;Cros MP;Zaridze D;Moukeria A;Boffetta P;Hainaut P;Brennan P;Herceg Z
烟碱型乙酰胆碱受体(NAChR)基因在肺癌易感基因15q25.1上形成高度保守的基因簇。在本研究中，我们发现编码nAChRα3亚单位的CHRNα3基因是肺癌中常见的异常甲基化和沉默的靶基因，而邻近的CHRNβ4和CHRNα5基因分别表现出中度甲基化和无甲基化。用α甲基化抑制剂处理出现CHRNα3高甲基化的癌细胞，可导致CHRN DNA 3启动子去甲基化和基因重新激活。通过异位表达恢复CHRNα3水平可诱导细胞凋亡。短发夹状RNA介导的nAChRα3缺失在表达α3的肺癌细胞中可在尼古丁存在的情况下引起显著的钙内流反应，随后激活Akt生存通路。CHRNα3缺失的细胞对凋亡诱导剂具有抵抗力，这突显了CHRNα3基因的表观遗传沉默在人类癌症中的重要性。在确定非神经元组织中nAChR表达的表观遗传控制机制方面，我们的发现提供了易感基因15q25.1与肺癌之间的功能联系，并提示nAChRs是癌症检测和化学预防的治疗靶点。
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 α 3 gene encoding nAChR α 3 subunit is a frequent target of aberrant DNA hypermethylation and silencing in lung cancer, whereas the adjacent CHRN β 4 and CHRN α 5 genes exhibit moderate and no methylation, respectively. Treatment of cancer cells exhibiting CHRN α 3 hypermethylation with DNA methylation inhibitors caused demethylation of the CHRN α 3 promoter and gene re-activation. Restoring CHRN α 3 levels through ectopic expression induced apoptotic cell death. shRNA-mediated depletion of nAChR α 3 in CHRN α 3-expressing lung cancer cells elicited a dramatic Ca2+ influx response in the presence of nicotine, followed by activation of the Akt survival pathway. CHRN α 3-depleted cells were resistant to apoptosis-inducing agents, underscoring the importance of epigenetic silencing of the CHRN α 3 gene in human cancer. In defining a mechanism of epigenetic control of nAChR expression in non-neuronal tissues, our findings offer a functional link between susceptibility locus 15q25.1 and lung cancer, and suggest nAChRs as theranostic targets for cancer detection and chemoprevention.