The Sulfotransferase Is Epigenetically Activated and Transcriptionally Induced by Tobacco Exposure and Is Associated with Patient Outcome in Lung Adenocarcinoma.

Lung cancer is the leading cause of cancer-related death. Tobacco exposure is associated with 80-90% of lung cancer cases. The sulfotransferase modifies xenobiotic compounds to enhance secretion but can also render these compounds carcinogenic. To determine if contributes to tobacco-related carcinogenesis in the lung, we analyzed the expression and epigenetic state of in human lung adenocarcinoma (LUAD) samples and in LUAD cell lines exposed to cigarette smoke condensate (CSC). expression was significantly positively correlated to overall LUAD patient survival in smokers, was elevated in LUAD tumors compared to adjacent non-tumor lung, and was significantly correlated with levels of patient exposure to tobacco smoke. promoter DNA methylation was inversely correlated with expression in LUAD, and hypomethylation of the promoter was observed in Asian patients, as compared to Caucasians. In vitro analysis of LUAD cell lines indicates that CSC stimulates expression of in a dose-dependent and cell-line-specific manner. In vitro methylation of the promoter significantly decreased transcriptional activity of a reporter plasmid, and expression was activated by the DNA demethylating agent 5-Aza-2'-deoxycytidine in a cell line in which the promoter was hypermethylated. An aryl hydrocarbon receptor (AHR) binding site was detected spanning critical methylation sites upstream of . CSC exposure significantly increased AHR binding to this predicted binding site in the promoter in multiple lung cell lines. Our data suggest that CSC exposure leads to activation of the AHR transcription factor, increased binding to the promoter, and upregulation of expression and that this process is inhibited by DNA methylation at the locus. Additionally, our results suggest that the level of promoter methylation and gene expression in normal lung varies depending on the race of the patient, which could in part reflect the molecular mechanisms of racial disparities seen in lung cellular responses to cigarette smoke exposure.