NAD-dependent methylenetetrahydrofolate dehydrogenase inhibits oral squamous cell carcinoma cell proliferation and promotes apoptosis

Background: NAD-dependent methylenetetrahydrofolate dehydrogenase catalyzes the conversion of 10-formyltetrahydrofolate to formate in embryonic and adult mammalian mitochondria. Methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) is a folate cycle enzyme that is involved in the development of various diseases including cancer. However, the specific mechanisms in oral squamous cell carcinoma (OSCC) are unclear. We analyzed the functional routes of MTHFD1L in OSCC cells. Methods: MTHFD1L expression in OSCC was analyzed using data from The Cancer Genome Atlas (TCGA) database. Then, the levels of mRNA were measured in OSCC and para-tumor oral tissues using Affymetrix microarrays. Additionally, the effects of short hairpin RNA (shRNA)-induced MTHFD1L silencing on the biological behavior of OSCC were assessed in vitro and in vivo, and the potential molecular mechanisms underlying MTHFD1L activity were also investigated. Results: A TCGA database analysis of RNA sequencing revealed that MTHFD1L levels were higher in tumor tissue than in adjacent tissues. Immunohistochemical staining and Kaplan-Meier survival analysis also indicated that MTHFD1L upregulation is associated with a poor prognosis in OSCC. The knockdown of MTHFD1L suppressed cell proliferation, colony formation, and tumorigenesis, while it induced apoptosis in OSCC. Mechanistically, a microarray analysis showed that MTHFD1L suppressed c-MYC and activated p53 signaling by regulating the protein expression of TP53, GADD45A, FAS and JUN. Conclusions: MTHFD1L may be involved in OSCC progression via the c-MYC gene and p53 signaling and may serve as a novel target and orientation for tumor therapy.