Epigenetic effects of chronic alcohol consumption on colonic mucosa

Summary

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

Top Publications

  1. pmc Ageing, chronic alcohol consumption and folate are determinants of genomic DNA methylation, p16 promoter methylation and the expression of p16 in the mouse colon
    Julia 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
  2. pmc Folate supplementation differently affects uracil content in DNA in the mouse colon and liver
    Kyong Chol Kim
    Department of Family Medicine, MizMedi Hospital, Seoul, South Korea
    Br J Nutr 105:688-93. 2011
  3. ncbi Oestrogen replacement therapy reduces total plasma homocysteine and enhances genomic DNA methylation in postmenopausal women
    Simonetta 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
  4. ncbi Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon
    Mary 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
  5. ncbi Mild depletion of dietary folate combined with other B vitamins alters multiple components of the Wnt pathway in mouse colon
    Zhenhua 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
  6. pmc Multiple B-vitamin inadequacy amplifies alterations induced by folate depletion in p53 expression and its downstream effector MDM2
    Zhenhua 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
  7. pmc 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
  8. pmc 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 modification
    Kyoung Jin Sohn
    Department of Medicine, University of Toronto, St Michael s Hospital, Toronto, Ontario, Canada
    Int J Cancer 124:1999-2005. 2009
  9. pmc DNA methylation, an epigenetic mechanism connecting folate to healthy embryonic development and aging
    Kyong 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

Scientific Experts

  • Simonetta Friso
  • Zhenhua Liu
  • SANG WOON CHOI
  • Kyong Chol Kim
  • Julia Sauer
  • Hyeran Jang
  • Donald E Smith
  • Joel B Mason
  • Aurelie Chanson
  • Ella M Zimmerly
  • Kyoung Jin Sohn
  • Mary K Keyes
  • Daniel J Weisenberger
  • Zoe Yates
  • Mark Lucock
  • Young In Kim
  • Jeffrey Dickhout
  • Richard C Austin
  • En Pei Chiang
  • Yi Cheng Wang
  • Peter W Laird
  • Robert C Cho
  • Mihaela Campan
  • Jimmy W Crott

Detail Information

Publications9

  1. pmc Ageing, chronic alcohol consumption and folate are determinants of genomic DNA methylation, p16 promoter methylation and the expression of p16 in the mouse colon
    Julia 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
    ....
  2. pmc Folate supplementation differently affects uracil content in DNA in the mouse colon and liver
    Kyong 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...
  3. ncbi Oestrogen replacement therapy reduces total plasma homocysteine and enhances genomic DNA methylation in postmenopausal women
    Simonetta 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
    ....
  4. ncbi Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon
    Mary 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...
  5. ncbi Mild depletion of dietary folate combined with other B vitamins alters multiple components of the Wnt pathway in mouse colon
    Zhenhua 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
    ....
  6. pmc Multiple B-vitamin inadequacy amplifies alterations induced by folate depletion in p53 expression and its downstream effector MDM2
    Zhenhua 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
    ....
  7. pmc 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...
  8. pmc 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 modification
    Kyoung Jin Sohn
    Department of Medicine, University of Toronto, St Michael s Hospital, Toronto, Ontario, Canada
    Int J Cancer 124:1999-2005. 2009
    ....
  9. pmc DNA methylation, an epigenetic mechanism connecting folate to healthy embryonic development and aging
    Kyong 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...