The integrity of the epigenome is maintained by a delicate balance between the extrinsic and intrinsic environment of the cell. Disruption of a cell's normal epigenetic programming results in alterations in gene expression, and depending on the genes affected, can eventually lead to disease, including cancer. There are many factors that reportedly alter the epigenetic status of DNA. Of particular importance is folate, and its synthetic form, folic acid. Folate is part of the one carbon cycle, and is ultimately the methyl donor for methylation reactions, including those of DNA and histones, two major targets of epigenetic modifiers. Although the U.S. food supply was subject to mandatory fortification with folic acid in 1998, little is known about the effects of extreme (high or low) folate levels. However, recent studies have shown that manipulation of dietary folic acid in the mouse can result in long-term epigenetic alterations. In addition, it seems that the changes that occur differ depending on the tissue type and the timing of dietary manipulation. The prostate has a particularly high requirement for folate, and also seems to be particularly susceptible to alterations in DNA methylation. We hypothesize that; (1) folate deficiency induces significant genomic DNA hypomethylation and site-specific aberrant DNA methylation that can lead to prostate cancer; and (2) excessive folic acid supplementation may accelerate prostate cancer progression from pre-neoplastic and neoplastic tissue, via epigenetic mechanisms. We have three specific aims: 1) To examine global and specific epigenetic changes in primary human prostate tissue (from cancer, normal tissue adjacent to cancer, and cancer-free donors) under different conditions of dietary folate (low, normal, high) when grown in the mouse. 2) To determine if the folate regulating enzyme PSMA mediates epigenetic changes when it induces invasive lesions in a transgenic tissue recombinant model and 3) To study the mechanism by which low extracellular folic acid levels result in epigenetic silencing of the ABCG2 gene. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA124892-02
Application #
7479874
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Ross, Sharon A
Project Start
2007-08-05
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$148,500
Indirect Cost
Name
University of Pittsburgh
Department
Urology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Yao, Veronica; Berkman, Clifford E; Choi, Joseph K et al. (2010) Expression of prostate-specific membrane antigen (PSMA), increases cell folate uptake and proliferation and suggests a novel role for PSMA in the uptake of the non-polyglutamated folate, folic acid. Prostate 70:305-16
Chang, Guimin; Xu, Shuping; Dhir, Rajiv et al. (2010) Hypoexpression and epigenetic regulation of candidate tumor suppressor gene CADM-2 in human prostate cancer. Clin Cancer Res 16:5390-401