Mouse models to elucidate mechanisms of folate-related cancer pathologies.

Perturbations in folate metabolism are associated with risk for colon cancer, although the underlying mechanisms remain to be established. It is not known if the associations between disruptions in folate metabolism and cancer result from altered S-adenosylmethionine (SAM; also known/abbreviated as AdoMet) synthesis and/or deoxythymidylic acid (dTMP) synthesis. Cytoplasmic serine hydroxymethyltransferase (cSHMT) is a metabolic switch that directs the partitioning of folateactivated one-carbon units between dTMP and SAM biosynthesis. cSHMT is expressed in tissues associated with folate-related pathologies, including the colon. Therefore, gain-of-function and loss-of-function cSHMT mouse models can be used to elucidate the contributions of the dTMP and SAM biosynthetic pathways to colon cancer. Nutrition and genetics interact to contribute to the initiation and progression of carcinogenesis. Molecular antecedents that promote the development of sporadic colon cancer include DNA damage (single point mutations, the loss of heterozygosity and microsatellite instability), and epigenetic alterations including chromatin methylation, which affect both genome stability and gene expression. Implicated in the development of cancer is the loss of function of the tumor suppressor genes adenomatous polyposis coli (APC) and p53, as well as epigenetic alterations, such as methylation of DNA that acts to silence tumor suppressor genes. Dietary deficiency of critical nutrients, including folate, and the generation of oxidative stress, increase rates of DNA damage and thereby have the potential to induce genetic mutations and instability that are responsible for the initiation and progression of carcinogenesis. Tetrahydrofolate (THF) serves as a cofactor that chemically activates and carries one-carbon units at three different oxidation levels for a network of reactions known as one-carbon metabolism, which occurs in the mitochondria and the cytoplasm (Figure 1).1,2 The primary role of mitochondrial one-carbon metabolism is to generate glycine and formate from serine.1,2 Mitochondrial-derived formate traverses to the cytoplasm where it is a major source of one-carbon units for cytoplasmic one-carbon metabolism.3–5 One-carbon metabolism in the cytoplasm is necessary for the de novo synthesis of purines (supplies carbon 2 and 8 of the purine ring) and thymidylate (methylation of dUMP (deoxyuridylic acid) to dTMP, and for the remethylation of homocysteine to methionine. Methionine can be adenylated to form SAM,which is a cofactor and one-carbon donor for numerous other methylation reactions.1,4,6,7