The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients

Ruo Kai Lin, Yi Shuan Hsieh, Pinpin Lin, Han Shui Hsu, Chih Yi Chen, Yen An Tang, Chung Fan Lee, Yi Ching Wang

研究成果: 雜誌貢獻文章

144 引文 (Scopus)

摘要

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 DNMT1 to recruit β-transducin repeat-containing protein (βTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3β function and thereby attenuating DNMT1 degradation. NNK also induced βTrCP translocation to the cytoplasm via the heterogeneous nuclear ribonucleoprotein U (hnRNP-U) shuttling protein, resulting in DNMT1 nuclear accumulation and hypermethylation of the promoters of tumor suppressor genes. Fluorescence immunohistochemistry (IHC) of lung adenomas from NNK-treated mice and tumors from lung cancer patients that were smokers were characterized by disruption of the DNMT1/βTrCP interaction and DNMT1 nuclear accumulation. Importantly, DNMT1 overexpression in lung cancer patients who smoked continuously correlated with poor prognosis. We believe that the NNK-induced DNMT1 accumulation and subsequent hypermethylation of the promoter of tumor suppressor genes may lead to tumorigenesis and poor prognosis and provide an important link between tobacco smoking and lung cancer. Furthermore, this mechanism may also be involved in other smoking-related human diseases.

原文英語
頁(從 - 到)521-532
頁數12
期刊Journal of Clinical Investigation
120
發行號2
DOIs
出版狀態已發佈 - 二月 1 2010
對外發佈Yes

指紋

Methyltransferases
Tumor Suppressor Genes
Carcinogens
Tobacco
Lung Neoplasms
DNA
Transducin
Glycogen Synthase Kinase 3
DNA Methylation
Heterogeneous-Nuclear Ribonucleoprotein U
Carcinogenesis
Smoking
Cell Line
Lung
Proteins
Protein Transport
Adenoma
Methylation
Neoplasms
Cytoplasm

ASJC Scopus subject areas

  • Medicine(all)

引用此文

The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients. / Lin, Ruo Kai; Hsieh, Yi Shuan; Lin, Pinpin; Hsu, Han Shui; Chen, Chih Yi; Tang, Yen An; Lee, Chung Fan; Wang, Yi Ching.

於: Journal of Clinical Investigation, 卷 120, 編號 2, 01.02.2010, p. 521-532.

研究成果: 雜誌貢獻文章

Lin, Ruo Kai ; Hsieh, Yi Shuan ; Lin, Pinpin ; Hsu, Han Shui ; Chen, Chih Yi ; Tang, Yen An ; Lee, Chung Fan ; Wang, Yi Ching. / The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients. 於: Journal of Clinical Investigation. 2010 ; 卷 120, 編號 2. 頁 521-532.
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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 DNMT1 to recruit β-transducin repeat-containing protein (βTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3β function and thereby attenuating DNMT1 degradation. NNK also induced βTrCP translocation to the cytoplasm via the heterogeneous nuclear ribonucleoprotein U (hnRNP-U) shuttling protein, resulting in DNMT1 nuclear accumulation and hypermethylation of the promoters of tumor suppressor genes. Fluorescence immunohistochemistry (IHC) of lung adenomas from NNK-treated mice and tumors from lung cancer patients that were smokers were characterized by disruption of the DNMT1/βTrCP interaction and DNMT1 nuclear accumulation. Importantly, DNMT1 overexpression in lung cancer patients who smoked continuously correlated with poor prognosis. We believe that the NNK-induced DNMT1 accumulation and subsequent hypermethylation of the promoter of tumor suppressor genes may lead to tumorigenesis and poor prognosis and provide an important link between tobacco smoking and lung cancer. Furthermore, this mechanism may also be involved in other smoking-related human diseases.",
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AU - Chen, Chih Yi

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AU - Lee, Chung Fan

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