2010
DOI: 10.1172/jci40706
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The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients

Abstract: DNA methyltransferase 1 (DNMT1) catalyzes DNA methylation and is overexpressed in many human diseases, including cancer. The tobacco-specific carcinogen NNK also induces DNA methylation. However, the role of DNMT1-mediated methylation in tobacco carcinogenesis remains unclear. Here we used human and mouse lung cancer samples and cell lines to determine a mechanism whereby NNK induced DNMT1 expression and activity. We determined that in a human lung cell line, glycogen synthase kinase 3β (GSK3β) phosphorylated … Show more

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Cited by 186 publications
(170 citation statements)
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“…NNK has been shown to induce lung carcinogenesis through both genetic and epigenetic mechanisms. Early changes during NNK-induced lung carcinogenesis include altered expression of DNMT1 and HDACs (41,42). Because CuB was found to alter the expression of DNMTs and HDACs in vitro, we selected an NNKinduced lung cancer mice model to assess the in vivo lung anticancer potential of CuB.…”
Section: Discussionmentioning
confidence: 99%
“…NNK has been shown to induce lung carcinogenesis through both genetic and epigenetic mechanisms. Early changes during NNK-induced lung carcinogenesis include altered expression of DNMT1 and HDACs (41,42). Because CuB was found to alter the expression of DNMTs and HDACs in vitro, we selected an NNKinduced lung cancer mice model to assess the in vivo lung anticancer potential of CuB.…”
Section: Discussionmentioning
confidence: 99%
“…The difference in the methylation frequency of MGMT gene among tobacco users and non users can be explained by the invitro study on mouse model and lung cancer tissues which revealed that NNK found in tobacco cause DNA methyl transferase I degradation and induces its nuclear accumulation resulting in hypermethylation of genes (Lin et al, 2010). Moreover, the nitrosamines present in tobacco is also responsible for causing the alkyl DNA damages and because MGMT plays an important role in the repair of O6 methyl guanine adduct formed due to nitrosamine carcinogen, its involvement in esophageal carcinogenesis is biologically plausible.…”
Section: Discussionmentioning
confidence: 99%
“…Tobacco contains more than 60 carcinogens (Hoffmann et al, 1990;Hecht et al, 2006) and tobacco exposure is known to induce genetic and epigenetic changes in esophageal squamous and lung cancer cells (Hecht et al, 1999;Soma et al, 2006;Liu et al, 2007;Lin et al, 2010;Huang et al, 2011). NNK is a key ingredient of tobacco smoke carcinogens.…”
Section: -(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Induces Retinmentioning
confidence: 99%
“…It is reported that NNK exposure can induce promoter hypermethylation of several tumor suppressor genes (TSGs) in lung and liver carcinomas, such as cyclin-dependent kinase inhibitor 2A and RARβ (Pulling et al, 2001;Hutt et al, 2005). Lin et al (2010) reported that NNK can induce TSGs promoter hypermethylation through the accumulation of DNMT1 in mice and human lung cancer. So we reasoned that NNK is likely to play a role in the carcinogenesis of ESCC.…”
Section: -(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Induces Retinmentioning
confidence: 99%