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- W2315852377 abstract "Epigenetic alterations are present at early stages of carcinogenesis, and DNA promoter hypermethylation in precursor lesions potentially affects transcriptional regulation. Previous studies by our laboratory have shown that the inhibitory neurotransmitter γ-aminobutyric acid (GABA) inhibits the proliferation of human pancreatic cancer cells grown both in vitro and in mouse xenografts. To test the hypothesis that nicotine as well as the nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induce changes in methylation status of the GABA synthesizing enzymes GAD1 (GAD67) and GAD2 (GAD65), the human pancreatic duct epithelial cell line clone HPDE6-E6E7c7 has been exposed to daily treatment of either nicotine or NNK over a course of five days. This initial screen of the methylation status of the promoter region of GAD1 and GAD2 by bisulfate genomic sequencing in HPDE6-E6E7c7 indicates aberrant methylation of GAD2 by either nicotine or NNK. Quantitative methylation-specific PCR as well as gene expression studies by real-time PCR after 5-aza-2’-deoxycytidine treatment, alone or in combination with trichostatin A on the last day of treatment along with concurrent five day treatment with nicotine or NNK confirm these observations that aberrant methylation of GAD2 may be an important factor in the pathogenesis of pancreatic cancer. Quantitative methylation-specific PCR indicates aberrant methylation in six out of ten human matched normal versus cancerous pancreatic tissue samples, which corroborates the in vitro results. In conclusion, exposure to nicotine and NNK leads to significant epigenetic alterations of the GAD2 promoter region. Consecutive silencing of GAD2 with suppression of GABA synthesis may represent an important mechanism by which nicotine and related compounds induce disturbances in inhibitory neurotransmitter circuits which may contribute to the pathogenesis of ductal adenocarcinoma of the pancreas. Supported by grants 1RO1CA130888 and 2RO1CA042829 with the National Cancer Institute. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 97. doi:10.1158/1538-7445.AM2011-97" @default.
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- W2315852377 date "2011-04-15" @default.
- W2315852377 modified "2023-09-26" @default.
- W2315852377 title "Abstract 97: Chronic nicotine and NNK exposure causes promoter hypermethylation of GAD2 in human pancreatic duct epithelial cells" @default.
- W2315852377 doi "https://doi.org/10.1158/1538-7445.am2011-97" @default.
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