Epigenetic effects of chronic alcohol consumption on colonic mucosa

描述（由申请人提供）：流行病学研究表明，饮酒可促进结直肠癌的发生，特别是在叶酸缺乏和/或亚甲基四氢叶酸还原酶（MTHFR）纯合变异基因型的个体中，这表明酒精的共致癌作用是通过叶酸介导的单碳代谢来传递的，同时也提倡酒精与MTHFR基因相互作用，维持生物甲基化和核苷酸合成之间的平衡。最近，我们发现慢性饮酒会导致啮齿动物结肠高同型半胱氨酸血症和基因组DNA低甲基化，这表明酒精对单碳代谢和表观遗传现象具有强大的影响，并随后证明慢性饮酒会通过表观遗传变化改变关键基因的表达，并在结肠粘膜中提供共同致癌环境。我们的长期目标是找到化学预防酒精相关癌症的有效策略。本提案中概述的研究旨在确定饮酒影响结直肠癌发生的表观遗传机制。因此，我们假设长期饮酒会扰乱结肠中的单碳代谢，从而改变表观遗传现象，包括DNA甲基化和组蛋白甲基化以及关键基因表达。我们进一步假设改变单碳代谢平衡的条件，如叶酸耗尽、衰老和MTHFR

DESCRIPTION (provided by applicant): Epidemiologic studies have demonstrated that alcohol consumption enhances colorectal carcinogenesis especially in individuals with folate depletion and/or methylenetetrahydrofolate reductase (MTHFR) homozygous variant genotype, indicating that the co-carcinogenic effect of alcohol is conveyed through the folate mediated one-carbon metabolism, as well as advocating an interaction between alcohol and MTHFR gene, which maintains a balance between biological methylation and nucleotide synthesis. Recently, we identified the fact that chronic alcohol consumption induces hyperhomocysteinemia and genomic DNA hypomethylation in the rodent colon, indicating the potent effects that alcohol exerts on onecarbon metabolism and epigenetic phenomena, and subsequently lending that chronic alcohol consumption modifies critical gene expression through epigenetic changes and provides a co-carcinogenic milieu in the colonic mucosa. Our long-term goal is to find effective strategies for the chemoprevention of alcohol-associated cancer. The studies outlined in this proposal are aimed at defining epigenetic mechanisms by which alcohol consumption affects colorectal carcinogenesis. We therefore hypothesize that chronic alcohol consumption disturbs one-carbon metabolism in the colon and thereby alters epigenetic phenomena including DNA methylation and histone methylation as well as critical gene expression. We further hypothesized that conditions which alter the balance of one-carbon metabolism, such as folate depletion, aging and MTHFR polymorphism, aggravate these epigenetic phenomena induced by chronic alcohol consumption. This application is innovative because two proposed epigenetic phenomena, histone methylation and promoter DNA methylation, have never been explored for the study regarding the alcohol-associated carcinogenesis and the proposed epigenetic interaction between alcohol and MTHFR gene is a new concept that enables individually tailored chemoprevention by genotypes and nutrition status. Based on the results of this application we will apply for a research project grant to finalize the epigenetic effect of chronic alcohol consumption on colorectal carcinogenesis. If those studies can precisely define the epigenetic mechanism for alcohol-associated carcinogenesis, we can develop a new chemopreventive strategy for those cancers.