Selenium (Se) is a dietary trace element that is recognized as having potential anticancer properties. Interest in selenium as a prostate cancer preventative nutrient is showcased by the recent initiation of the SELECT trial by NCI (http://newscenter.cancer.gov/pressreleases/SELECT.html). While selenium is known to modify several aspects of the cancer process, which is most critical for bringing about a phenotypic change remains to be established. Interestingly, increased selenium concentrations inhibit Dnmt1 activity in vitro. Consistent with these data, selenium deficiency has been shown to increase Dnmt protein expression in a human colon adenoma cell line. It is of further interest that selenium deprivation can lead to global hypomethylation in liver DNA, increased SAM/SAH ratios, and decreased homocysteine levels in the rat model.More information is needed about how diet impacts the regulation of DNA methylation processes. Probing studies about the activity of Se in regulating DNA methylation processes, as well as interactions between Se and other nutrients known to influence methyl supply, i.e., folate, remain to be performed. The outcome of this collaboration will assist in the elucidation of mechanism(s) by which specific dietary factors influence DNA methylation processes as well as increasing our understanding of these processes in cancer prevention. Statement of Work: Selenium will be evaluated for its role in cancer susceptibility, gene expression, DNA methylation, and one-carbon metabolism. Animal and cell culture studies, biochemical and molecular analyses will be performed at the USDA, ARS Grand Forks Human Nutrition Research Center. The NCI will pay for the part of the laboratory costs associated with these analyses. Studies, done in collaboration with Drs. Eric Uthus and Huawei Zeng (USDA) and Dr. Sharon Ross (NCI), will consist of exploratory work to determine the feasibility of various animal models (e.g., multiple intestinal neoplasia (Min) mice, methionine sulfoxide reductase knockout mice, DNA methyltransferase knockout mice, Ames dwarf mice) and cell culture models (e.g., Caco-2 or HT29 colon cancer cells and CCD 841 CoN cells ) on cancer susceptibility as measured by gene expression, global and gene specific DNA methylation, DNA methyltransferase activity, and one-carbon metabolism in various tissues or cells, and cell cycle and apoptosis in cell culture. Funds will be used to purchase animals and for reagents, supplies, and equipment to perform the gene expression, DNA methylation, , enzyme, and metabolite analysis, and cell culture studies. Funds may also be used to partially offset the salary of a post-doctoral research associate to carry out the analyses.
