Epigenetic effects of chronic alcohol consumption on colonic mucosa
Principal Investigator: SANG WOON CHOI
Abstract: [unreadable] 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 [unreadable] 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. [unreadable] [unreadable] [unreadable]
Funding Period: 2006-09-30 - 2010-02-28
more information: NIH RePORT
- Ageing, chronic alcohol consumption and folate are determinants of genomic DNA methylation, p16 promoter methylation and the expression of p16 in the mouse colonJulia Sauer
Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA
Br J Nutr 104:24-30. 2010....
- Folate supplementation differently affects uracil content in DNA in the mouse colon and liverKyong Chol Kim
Department of Family Medicine, MizMedi Hospital, Seoul, South Korea
Br J Nutr 105:688-93. 2011..Further studies are needed to clarify the significance of increased uracil misincorporation into colonic DNA of folate-supplemented young mice...
- Oestrogen replacement therapy reduces total plasma homocysteine and enhances genomic DNA methylation in postmenopausal womenSimonetta Friso
Department of Clinical and Experimental Medicine, University of Verona School of Medicine, Policlinico G B Rossi, P le L A Scuro 10, 37134 Verona, Italy
Br J Nutr 97:617-21. 2007....
- Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colonMary K Keyes
Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02478, USA
J Nutr 137:1713-7. 2007..041), but not in the folate-deplete group. In conclusion, aging decreases genomic DNA methylation and increases promoter methylation and expression of p16 in mouse colons. This effect is dependent on the level of dietary folate...
- Mild depletion of dietary folate combined with other B vitamins alters multiple components of the Wnt pathway in mouse colonZhenhua Liu
Vitamins and Carcinogenesis Laboratory, Jean Mayer U S Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA
J Nutr 137:2701-8. 2007....
- Multiple B-vitamin inadequacy amplifies alterations induced by folate depletion in p53 expression and its downstream effector MDM2Zhenhua Liu
Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA
Int J Cancer 123:519-25. 2008....
- Too much folate: a risk factor for cancer and cardiovascular disease?Julia Sauer
Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111, USA
Curr Opin Clin Nutr Metab Care 12:30-6. 2009..The intent of this evidence-based review is to analyze the role of folate in chronic diseases, focusing on cancer and cardiovascular disease...
- The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: a possible molecular basis for the site-specific cancer risk modificationKyoung Jin Sohn
Department of Medicine, University of Toronto, St Michael s Hospital, Toronto, Ontario, Canada
Int J Cancer 124:1999-2005. 2009....
- DNA methylation, an epigenetic mechanism connecting folate to healthy embryonic development and agingKyong Chol Kim
Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA
J Nutr Biochem 20:917-26. 2009..In this review, we address the effect of folate on early development and aging through an epigenetic mechanism, DNA methylation...