Citations to this article


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.


Ruo-Kai Lin ... Chung-Fan Lee, Yi-Ching Wang


Total citations by year in Crossref

Year: 2015 2014 2013 2012 2011 2010 Total
Citations: 1 10 5 8 4 4 32
Citation information

Citations to this article in Crossref (32)

Title and authors Publication Year
Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases
E Beurel, SF Grieco, RS Jope
Pharmacology & Therapeutics 2015
Time to first cigarette predicts 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in adolescent regular and intermittent smokers, National Health and Nutrition and Examination Survey (NHANES) 2007-10: Time to first cigarette and NNAL
SA Branstetter, M Mercincavage, JE Muscat
Addiction 2014
p16 hypermethylation: A biomarker for increased esophageal cancer susceptibility in high incidence region of North East India
M Das, BJ Saikia, SK Sharma, GS Sekhon, J Mahanta, RK Phukan
Tumor Biology 2014
NNK-Induced DNA Methyltransferase 1 in Lung Tumorigenesis in A/J Mice and Inhibitory Effects of (−)-Epigallocatechin-3-Gallate
H Jin, JX Chen, H Wang, G Lu, A Liu, G Li, S Tu, Y Lin, CS Yang
Nutrition and Cancer 2014
miR-199a-5p Silencing Regulates the Unfolded Protein Response in Chronic Obstructive Pulmonary Disease and α 1 -Antitrypsin Deficiency
T Hassan, TP Carroll, PG Buckley, R Cummins, SJ O’Neill, NG McElvaney, CM Greene
American journal of respiratory and critical care medicine 2014
Akt1 mediates the posterior Hoxc gene expression through epigenetic modifications in mouse embryonic fibroblasts
KA Kong, J Lee, JH Oh, Y Lee, MH Kim
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 2014
Gallic acid protects against endothelial injury by restoring the depletion of DNA methyltransferase 1 and inhibiting proteasome activities
A Kam, KM Li, V Razmovski-Naumovski, S Nammi, K Chan, GQ Li
International Journal of Cardiology 2014
‘Default’ generated neonatal regulatory T cells are hypomethylated at conserved non-coding sequence 2 and promote long-term cardiac allograft survival
C Cheng, S Wang, P Ye, X Huang, Z Liu, J Wu, Y Sun, A Xie, G Wang, J Xia
Immunology 2014
Epigenetics of lung cancer
SM Langevin, RA Kratzke, KT Kelsey
Translational Research 2014
Epigenetic mechanisms in COPD: implications for pathogenesis and drug discovery
AC Schamberger, N Mise, S Meiners, O Eickelberg
Expert Opinion on Drug Discovery 2014
IP Pogribny, T Kobets, FA Beland
Encyclopedia of Life Sciences 2014
Epigenetics and pesticides
M Collotta, PA Bertazzi, V Bollati
Toxicology 2013
Tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone suppresses a newly identified anti-tumor IGFBP-3/IGFBP-3R system in lung cancer cells
A Harada, S Jogie-Brahim, Y Oh
Lung Cancer 2013
Zebularine inhibits the growth of A549 lung cancer cells via cell cycle arrest and apoptosis: Zeb INHIBITS THE GROWTH OF A549 LUNG CANCER CELLS
BR You, WH Park
Molecular Carcinogenesis 2013
Zebularine-induced apoptosis in Calu-6 lung cancer cells is influenced by ROS and GSH level changes
BR You, WH Park
Tumor Biology 2013
Down-regulation of DNA methyltransferase 3B in staurosporine-induced apoptosis and its mechanism in human hepatocarcinoma cell lines
C Zhao, P Yin, C Mei, N Li, W Yao, X Li, J Qi, K Fan, Z Li, L Wang, Y Shi, S Qiu, J Fan, X Zha
Molecular and Cellular Biochemistry 2013
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Induces Retinoic Acid Receptor β Hypermethylation through DNA Methyltransferase 1 Accumulation in Esophageal Squamous Epithelial Cells
J Wang, SL Zhao, Y Li, M Meng, CY Qin
Asian Pacific Journal of Cancer Prevention 2012
Akt1 as a putative regulator of Hox genes
KA Kong, H Yoon, MH Kim
Gene 2012
DNA methylome alterations in chemical carcinogenesis
IP Pogribny, FA Beland
Cancer Letters 2012
Targeting epigenetic mediators of gene expression in thoracic malignancies
DS Schrump
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 2012
The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation in Laryngeal carcinoma
J Wang, Y Xu, J Li, X Sun, LP Wang, WY Ji
Oral Oncology 2012
Cigarette Smoke-Induced Failure of Apoptosis Resulting in Enhanced Neoplastic Transformation in Human Bronchial Epithelial Cells
H Du, J Sun, Z Chen, J Nie, J Tong, J Li
Journal of Toxicology and Environmental Health, Part A 2012
Influences of tobacco and alcohol use on hepatocellular carcinoma survival
WL Shih, HC Chang, YF Liaw, SM Lin, SD Lee, PJ Chen, CJ Liu, CL Lin, MW Yu
International Journal of Cancer 2012
Zebularine inhibits the growth of HeLa cervical cancer cells via cell cycle arrest and caspase-dependent apoptosis
BR You, WH Park
Molecular Biology Reports 2012
Expression and regulation of DNA methyltransferases in human endometrium
ZL Vincent, CM Farquhar, MD Mitchell, AP Ponnampalam
Fertility and Sterility 2011