Shmt1 heterozygosity impairs folate-dependent thymidylate synthesis capacity and modifies risk of Apc(min)-mediated intestinal cancer risk

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-03, Vol.71 (6), p.2098-2107
• Main Authors: Macfarlane, Amanda J, Perry, Cheryll A, McEntee, Michael F, Lin, David M, Stover, Patrick J
• Format: Article
• Language: English
• Subjects: Adenomatous Polyposis Coli Protein - genetics; Adenomatous Polyposis Coli Protein - metabolism; Animals; Blotting, Western; Cells, Cultured; Colon - metabolism; Colon - pathology; Diet; Enterocytes - metabolism; Epithelial Cells - metabolism; Female; Folic Acid - metabolism; Gene Expression Profiling; Glycine Hydroxymethyltransferase - genetics; Glycine Hydroxymethyltransferase - metabolism; Heterozygote; Immunohistochemistry; Intestinal Neoplasms - genetics; Intestinal Neoplasms - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Oligonucleotide Array Sequence Analysis; Purines - biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Thymine Nucleotides - biosynthesis
• ISSN: 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-1886

Folate-mediated one-carbon metabolism is required for the de novo synthesis of purines, thymidylate, and S-adenosylmethionine, the primary cellular methyl donor. Impairments in folate metabolism diminish cellular methylation potential and genome stability, which are risk factors for colorectal cancer (CRC). Cytoplasmic serine hydroxymethyltransferase (SHMT1) regulates the partitioning of folate-activated one-carbons between thymidylate and S-adenosylmethionine biosynthesis. Therefore, changes in SHMT1 expression enable the determination of the specific contributions made by thymidylate and S-adenosylmethionine biosynthesis to CRC risk. Shmt1 hemizygosity was associated with a decreased capacity for thymidylate synthesis due to downregulation of enzymes in its biosynthetic pathway, namely thymidylate synthase and cytoplasmic thymidine kinase. Significant Shmt1-dependent changes to methylation capacity, gene expression, and purine synthesis were not observed. Shmt1 hemizygosity was associated with increased risk for intestinal cancer in Apc(min)(/+) mice through a gene-by-diet interaction, indicating that the capacity for thymidylate synthesis modifies susceptibility to intestinal cancer in Apc(min)(/+) mice.