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

Abstract

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.

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process

“…In this, we found five completely consistent proteins common across all the GPR19 expression doses in all three distinct cell compartment extracts: MDC1; MTHFD1L; PDCD5; ANP32C; MGEA5; SETBP1. Consistent with the overall molecular phenotype of GPR19, many of these proteins are linked to DNA damage [22,[50][51][52], energy metabolism [53][54][55][56][57][58][59], and oncology [60][61][62][63][64][65]. Generating a heatmap of these conserved DEPs, it was evident that a diverse array of expression polarities were found for these proteins across the distinct GPR19 expression doses/compartment extracts (Figure S3B).…”

Identification of MTHFD1L as a potential biomarker for multiple cancers by pan-cancer analysis

“…Inversely, MTHFD1L knockdown signi cantly decreased the tumor cell growth in papillary thyroid cancer (PTC) [23] . Similarly, decreased expression of MTHFD1L suppressed the tumor cell proliferation and promoted apoptosis in OSCC (oral squamous cell carcinoma) [24] . However, there are not systematic analysis about the functional roles of MTHFD1L in all kinds of cancer types.…”

Salivary Metabolomics for Oral Cancer Detection: A Narrative Review

“…These enzymes are activated downstream of several oncogenes, such as c-MYC and Tp53 [ 86 ]. These oncogenes have been associated with OC promotion and progression [ 87 , 88 ]. Therefore, elevated levels of metabolites involved in these pathways are expected, and their use as biomarker should be explored.…”