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

Year: 2015 2014 2013 2012 2011 2010 Total
Citations: 2 19 16 17 13 6 73
Citation information

Citations to this article in year 2011 (13)

Title and authors Publication Year
Expression and regulation of DNA methyltransferases in human endometrium
ZL Vincent, CM Farquhar, MD Mitchell, AP Ponnampalam
Fertility and Sterility 2011
From Smoking to Cancers: Novel Targets to Neuronal Nicotinic Acetylcholine Receptors
CH Lee, CH Wu, YS Ho
Journal of Oncology 2011
Lung cancer and its association with chronic obstructive pulmonary disease: update on nexus of epigenetics
IK Sundar, N Mullapudi, H Yao, SD Spivack, I Rahman
Current Opinion in Pulmonary Medicine 2011
O6-methylguanine-DNA methyltransferase (MGMT): impact on cancer risk in response to tobacco smoke
M Christmann, B Kaina
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 2011
Interaction of Cigarette Exposure and Airway Epithelial Cell Gene Expression
JS Brody, K Steiling
Annual Review of Physiology 2011
Genetic and epigenetic changes in lung carcinoma and their clinical implications
J Wen, J Fu, W Zhang, M Guo
Modern Pathology 2011
Overexpression and small molecule-triggered downregulation of CIP2A in lung cancer
L Ma, ZS Wen, Z Liu, Z Hu, J Ma, XQ Chen, YQ Liu, JX Pu, WL Xiao, HD Sun, GB Zhou
PloS one 2011
O-methylguanine-DNA methyltransferase (MGMT) mRNA expression predicts outcome in malignant glioma independent of MGMT promoter methylation
S Kreth, N Thon, S Eigenbrod, J Lutz, C Ledderose, R Egensperger, JC Tonn, HA Kretzschmar, LC Hinske, FW Kreth
PloS one 2011
Lysyl oxidase, a critical intra- and extra-cellular target in the lung for cigarette smoke pathogenesis
W Li, J Zhou, L Chen, Z Luo, Y Zhao
International journal of environmental research and public health 2011
TGF-β Regulates DNA Methyltransferase Expression in Prostate Cancer, Correlates with Aggressive Capabilities, and Predicts Disease Recurrence
Q Zhang, L Chen, BT Helfand, TL Jang, V Sharma, J Kozlowski, TM Kuzel, LJ Zhu, XJ Yang, B Javonovic, Y Guo, S Lonning, J Harper, BA Teicher, C Brendler, N Yu, WJ Catalona, C Lee
PloS one 2011
Loss of Glucocorticoid Receptor Expression by DNA Methylation Prevents Glucocorticoid Induced Apoptosis in Human Small Cell Lung Cancer Cells
P Kay, G Schlossmacher, L Matthews, P Sommer, D Singh, A White, D Ray
PloS one 2011
Cigarette Smoking and p16INK4α Gene Promoter Hypermethylation in Non-Small Cell Lung Carcinoma Patients: A Meta-Analysis
B Zhang, W Zhu, P Yang, T Liu, M Jiang, ZN He, SX Zhang, WQ Chen, W Chen
PloS one 2011
SAF-A Forms a Complex with BRG1 and Both Components Are Required for RNA Polymerase II Mediated Transcription
D Vizlin-Hodzic, R Runnberg, J Ryme, S Simonsson, T Simonsson
PloS one 2011