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Carcinogenesis Advance Access published online on January 19, 2008
Carcinogenesis, doi:10.1093/carcin/bgn012
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Epigenetic silencing of O6-methylguanine-DNA methyltransferase gene in NiS-transformed cells

Weidong Ji1,2,3, Linqing Yang2, Lei Yu2, Jianhui Yuan2, Dalin Hu1, Wenjuan Zhang1, Jianping Yang1, Yaqin Pang1, Wenxue Li1, Jiachun Lu3, Juan Fu3, Jiakun Chen3, Zhongning Lin1, Wen Chen1,* and Zhixiong Zhuang1,2,*

1 Faculty of Preventive Medicine, School of Public Health, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou 510080, P.R.China
2 Shenzhen Center for Disease Control and Prevention, 21 Tianbei Road 1, Shenzhen 518020, P.R.China
3 Institute for Chemical Carcinogenesis, Guangzhou Medical College, 195 Dongfeng Xi Road, Guangzhou 510182, P.R.China

* To whom correspondence should be address. Tel: +011 086 0755 25639066; Email: zxzhuang2007{at}126.com (Zhixiong Zhuang) or Tel: +011 86 20 87330599; Fax:+011 86 20 87330446; Email: wenchen1107{at}163.com (Wen Chen)

Nickel (Ni) compounds are potent carcinogens and can induce malignant transformation of rodent and human cells. To uncover the molecular mechanisms of nickel sulfide (NiS)-induced cell transformation, we investigated epigenetic alterations in a set of DNA repair genes. The silencing of the O6-methylguanine DNA methyltransferase (MGMT) gene locus and up-regulation of DNA methyltransferase 1 (DNMT1) expression was specifically detected in NiS-transformed human bronchial epithelial cells (16HBE). In addition, we noted epigenetic alterations including DNA hypermethylation, reduced histone H4 acetylation, and a decrease in the ratio of Lys-9 acetylated/methylated histone H3 at the MGMT CpG island in NiS-transformed 16HBE cells. Meanwhile, we identified concurrent binding of methyl-CpG binding protein 2 (MeCP2), methylated DNA-binding domain protein 2 (MBD2) and DNMT1 to the CpG island of the MGMT promoter, demonstrating that these components collaborate to maintain MGMT methylation in NiS-transformed cells. Moreover, depletion of DNMT1 by introduction of a shRNA construct into NiS-transformed cells resulted in a 30% inhibition of cell proliferation and led to increased MGMT gene expression by reversion of the epigenetic modifications at the MGMT promoter region. MGMT suppression and hypermethylation at the CpG island of the MGMT promoter occurred 6 d after NiS treatment, indicating that epigenetic modifications of MGMT might be an early event in tumorigenesis. Taken together, these observations demonstrate that epigenetic silencing of MGMT is associated with DNA hypermethylation, histone modifications, and DNMT1 up-regulation, which contribute to NiS-induced malignant transformation.

Key Words: cell transformation • epigenetic • methylation • O6-methylguanine-DNA methyltransferase (MGMT) • nickel sulfide (NiS)

Contact information: Zhixiong Zhuang, M.D., Ph.D., Shenzhen Center for Disease Control and Prevention, 21Tianbei Road 1, Shenzhen 518020, P. R.China. Tel: 011-86-0755-25639066. Fax: 011-86-0755-25639066. Email: zxzhuang2007{at}126.com

Received September 20, 2007; revised December 4, 2007; accepted December 27, 2007.


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