Folate-Genome Interactions in Colorectal Cancer

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DESCRIPTION (provided by applicant): This research aims to elucidate the molecular mechanisms that account for the associations between impaired folate status and risk for colon cancer using purpose-designed mouse models. Folate metabolism is necessary for the synthesis of nucleotides (purines and dTMP) and S-adenosylmethionine (SAM). Disruption of folate metabolism by vitamin deficiency or single nucleotide polymorphisms can affect SAM and dTMP syntheses and thereby influence DNA methylation density and uracil content. Both DNA uracil content and methylation density affect DNA stability, and DNA methylation also regulates the expression of many genes. It is not known if the associations between folate and colon cancer risk result from altered SAM synthesis and/or dTMP synthesis. Recently, we have demonstrated that the enzyme cytoplasmic serine hydroxymethyltransferase (cSHMT) is a metabolic switch that directs the flux of folate-activated one-carbon units between dTMP and SAM biosynthetic pathways, cSHMT expression and activity is regulated by several dietary components including retinoic acid, iron/ferritin and vitamin B6. Therefore, the eSHMTmediated metabolic switch is likely involved in the etiology of folate-related pathologies and may be a target for prevention. In this proposal, we will determine the metabolic role of eSHMT in regulating folate metabolism, DNA and histone methylation, DNA stability and gene expression in the colonic crypts and determine if disruption of either dTMP or SAM synthesis increases (or protects against) colon cancer incidence in established mouse cancer models. The principle hypotheses to be tested are that: (1). cSHMT regulates folate metabolism in the colonic crypt. (2). cSHMT expression is regulated in the crypts of the colon by ferritin and influences cancer risk. (3). changes in cSHMT influences genomic methylation, expression and stability in the colonic crypt. The long-term goal of this project is: (1). to determine the mechanism whereby alterations in folate metabolism influence cancer risk.