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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 theO  6-methylguanine DNA methyltransferase (MGMT) gene locus and upregulation of DNA methyltransferase 1 (DNMT1) expression was specifically detected in NiS-transformed human bronchial epithelial (16HBE) cells. 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 theMGMTCpG island in NiS-transformed 16HBE cells. Meanwhile, we identified concurrent binding of methyl-CpG-binding protein 2, methylated DNA-binding domain protein 2 and DNMT1 to the CpG island of theMGMTpromoter, demonstrating that these components collaborate to maintainMGMTmethylation in NiS-transformed cells. Moreover, depletion ofDNMT1by introduction of a small hairpin RNA construct into NiS-transformed cells resulted in a 30% inhibition of cell proliferation and led to increasedMGMTgene expression by reversion of the epigenetic modifications at theMGMTpromoter region.MGMTsuppression and hypermethylation at the CpG island of theMGMTpromoter occurred 6 days after NiS treatment, indicating that epigenetic modifications ofMGMTmight be an early event in tumorigenesis. Taken together, these observations demonstrate that epigenetic silencing ofMGMTis associated with DNA hypermethylation, histone modifications andDNMT1upregulation, which contribute to NiS-induced malignant transformation.

Epigenetic silencing of O 6 -methylguanine DNA methyltransferase gene in NiS-transformed cells