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.

Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis

“…Consistent with these findings, previous studies of the Mthfd1 gt/+ mouse model showed that a 50% reduction in MTHFD1 protein led to reduced hepatic S-adenosylmethionine levels (21), lower methylation potential (19), elevated plasma homocysteine (22), and lower levels of methionine (23), indicating impaired function of the homocysteine remethylation cycle. However, the proband exhibited relatively mild elevations in plasma homocysteine concurrent with lower serum methionine and elevated homocysteine (8).…”

Nuclear Enrichment of Folate Cofactors and Methylenetetrahydrofolate Dehydrogenase 1 (MTHFD1) Protect de Novo Thymidylate Biosynthesis during Folate Deficiency

“…Surprisingly, Mthfd1 gt/ϩ animals do not develop neural tube defects even when fed a folate-deficient diet (28) and exhibit decreased levels of uracil in nuclear DNA in both liver (Table 3) and colon (23). The decrease in uracil in DNA is not explained by increased thymidylate salvage pathway activity as thymidine kinase 1 is not up-regulated in Mthfd1 gt/ϩ liver (Fig.…”

“…gt/ϩ mice accumulate less uracil in colon genomic DNA as compared with Mthfd1 ϩ/ϩ littermates (23). Here it is shown that Mthfd1 gt/ϩ liver DNA is also resistant to uracil accumulation Values are represented as the mean Ϯ S.D.…”

Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

“…DHF reductase (DHFR) reduces DHF to THF. 5,10-methyleneTHF can be regenerated either from serine and THF through the activity of serine hydroxymethyltransferase (SHMT1 or SHMT2α) or from formate, ATP, NADPH, and THF by the activity of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) (4)(5)(6). SHMT1, DHFR, and TYMS are small ubiquitin-like modifier (SUMO)-ylated and translocate to the nucleus at the G1/S boundary (7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”