title: Mthfd1 is a modifier of chemically induced intestinal carcinogenesis.
abstract: The causal metabolic pathways underlying associations between folate and risk for colorectal cancer (CRC) have yet to be established. Folate-mediated one-carbon metabolism is required for the de novo synthesis of purines, thymidylate and methionine. Methionine is converted to S-adenosylmethionine (AdoMet), the major one-carbon donor for cellular methylation reactions. Impairments in folate metabolism can modify DNA synthesis, genomic stability and gene expression, characteristics associated with tumorigenesis. The Mthfd1 gene product, C1-tetrahydrofolate synthase, is a trifunctional enzyme that generates one-carbon substituted tetrahydrofolate cofactors for one-carbon metabolism. In this study, we use Mthfd1(gt/+) mice, which demonstrate a 50% reduction in C1-tetrahydrofolate synthase, to determine its influence on tumor development in two mouse models of intestinal cancer, crosses between Mthfd1(gt/+) and Apc(min)(/+) mice and azoxymethane (AOM)-induced colon cancer in Mthfd1(gt/+) mice. Mthfd1 hemizygosity did not affect colon tumor incidence, number or load in Apc(min/+) mice. However, Mthfd1 deficiency increased tumor incidence 2.5-fold, tumor number 3.5-fold and tumor load 2-fold in AOM-treated mice. DNA uracil content in the colon was lower in Mthfd1(gt/+) mice, indicating that thymidylate biosynthesis capacity does not play a significant role in AOM-induced colon tumorigenesis. Mthfd1 deficiency-modified cellular methylation potential, as indicated by the AdoMet: S-adenosylhomocysteine ratio and gene expression profiles, suggesting that changes in the transcriptome and/or decreased de novo purine biosynthesis and associated mutability cause cellular transformation in the AOM CRC model. This study emphasizes the impact and complexity of gene-nutrient interactions with respect to the relationships among folate metabolism and colon cancer initiation and progression.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: MacFarlane
authors.forename: Cheryll A
authors.initials: CA
authors.lastname: Perry
authors.forename: Michael F
authors.initials: MF
authors.lastname: McEntee
authors.forename: David M
authors.initials: DM
authors.lastname: Lin
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Stover
mesh_terms: D000619:Aminohydrolases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001397:Azoxymethane / Q000633:toxicity; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004273:DNA, Neoplasm / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005574:Formate-Tetrahydrofolate Ligase / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D007124:Immunoenzyme Techniques; D008297:Male; D045064:Methenyltetrahydrofolate Cyclohydrolase / Q000235:genetics / Q000502:physiology*; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000235:genetics / Q000502:physiology*; D064251:Multifunctional Enzymes / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism*; D014498:Uracil / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D002273:Carcinogens; D004273:DNA, Neoplasm; C000622271:Mthfd1 protein, mouse; D009097:Multienzyme Complexes; D064251:Multifunctional Enzymes; D012333:RNA, Messenger; D014498:Uracil; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases; D045064:Methenyltetrahydrofolate Cyclohydrolase; D005574:Formate-Tetrahydrofolate Ligase; D001397:Azoxymethane