The tobacco-specific carcinogen NNK may promote lung-tumor formation and development by inducing the accumulation of the DNA methyltransferase 1 (DNMT1) protein in the nucleus, report researchers from National Cheng Kung University, Taiwan. They explain that DNMT1 silences genes that suppress tumor formation.
The study, appearing in the January 19 edition of The Journal of Clinical Investigation, is titled “The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients.”
DNMT1 catalyzes DNA methylation and is overexpressed in many human diseases including cancer. NNK also induces DNA methylation, however, the role of DNMT1-mediated methylation in tobacco carcinogenesis has remained unclear.
In this study, the scientists found that in a human lung cell line, glycogen synthase kinase 3β (GSK3β) phosphorylated DNMT1 to recruit β-transducin repeat-containing protein (βTrCP). This resulted in DNMT1 degradation. NNK activated AKT, inhibiting GSK3β function and thereby attenuating DNMT1 degradation.
The authors also found that NNK induced βTrCP translocation to the cytoplasm, resulting in DNMT1 accumulation in the nucleus as well as hypermethylation of tumor-suppressor gene promoters.
Fluorescence immunohistochemistry of lung adenomas from NNK-treated mice and tumors from lung-cancer patients who were smokers were both characterized by disruption of the DNMT1/βTrCP interaction and DNMT1 nuclear accumulation, the researchers report. Importantly, DNMT1 overexpression in lung-cancer patients who smoked continuously correlated with poor prognosis.
The authors believe that their findings provide an important link between tobacco smoking and lung cancer and that this mechanism may also be involved in other smoking-related human diseases.