Methylenetetrahydrofolate Dehydrogenase 1 Silencing Expedites the Apoptosis of Non-Small Cell Lung Cancer Cells via Modulating DNA Methylation

Abstract

BackgroundNon-small cell lung cancer (NSCLC) accounts for about 85% of all types of lung cancer. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) is involved in DNA methylation, and DNA methylation is related to tumorigenesis. The role of MTHFD1 in NSCLC was examined in our study.Material/MethodsThe correlation between the expression of MTHFD1 and the clinicopathological features of patients diagnosed with lung cancer was investigated using the chi-square test. The viability and apoptosis of NCI-H1299 cells was respectively detected using cell counting kit-8 and flow cytometry assays. The expression levels of MTHFD1, apoptosis-related factors and DNA methyltransferase-related factors were assessed by quantitative real-time PCR (qRT-PCR) and western blot assays.ResultsWe found that MTHFD1 expression in the tumor tissues and cells was higher than that of adjacent normal tissues and cells. The survival time of patients with high MTHFD1 expression was shorter than those with low MTHFD1 expression. The expression level of MTHFD1 was related to tumor size, TNM stage, histologic grade, and metastasis, but not linked to gender and age. Besides, si-MTHFD1 significantly decreased the viability of cells in a time-dependent manner, and increased cell apoptosis. When cells were transfected with MTHFD1-siRNA, the levels of surviving and B-cell lymphoma-2 (Bcl-2) were attenuated, while p53 and Bcl-2 associated X protein (Bax) levels were enhanced. Moreover, si-MTHFD1 markedly downregulated the expression levels of DNA methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b.ConclusionsCollectively, our results proved that MTHFD1 silencing obviously reduced the proliferation and enhanced the apoptosis of NSCLC via suppressing DNA methylation.

Long Non-Coding RNAs (lncRNAs) Tumor-Suppressive Role of lncRNA on Chromosome 8p12 (TSLNC8) Inhibits Tumor Metastasis and Promotes Apoptosis by Regulating Interleukin 6 (IL-6)/Signal Transducer and Activator of Transcription 3 (STAT3)/Hypoxia-Inducible Factor 1-alpha (HIF-1α) Signaling Pathway in Non-Small Cell Lung Cancer

“…Lung cancer is one of the most common and aggressive tumors worldwide, with extremely high morbidity and mortality rates [1]. Among diagnosed lung cancer cases, approximately 80–85% are non-small cell lung cancer (NSCLC) [2–4]. Although advances in diagnosis and treatment have been made in NSCLC, the 5-year survival rate and recurrence rate remain poor [5].…”

Single-nucleotide polymorphisms in one-carbon metabolism genes, Mediterranean diet and the risk of pre- and postmenopausal breast cancer

“…It usually catalyzes sequential and reversible reactions in multiple conversion of tetrahydrofolate (THF), the active form of folate, into 5,10 methylene-THF, which is essential for the de novo purine and thymidylate synthesis as well as the supply of one-carbon units for subsequent DNA methylation. The de ciency or dysregulation of the MTHFD1 enzyme may in uence cell division and global methylation pattern, eventually contributing to tumorigenesis (Ding, et al 2018, MacFarlane, et al 2011). Since rs8003567 located in the intronic region of the MTHFD1 gene and no disease-related studies on SNPs have been reported before, another possible explanation cannot be excluded that there are additional functional genetic variants in linkage disequilibrium with these two SNPs that modify BC risk in Chinese female population.…”

MTHFD1L-Mediated Redox Homeostasis Promotes Tumor Progression in Tongue Squamous Cell Carcinoma

“…The epigenetic regulation of metabolism-related genes has also been reported in several studies that have attracted our attention. MTHFD1L silencing reduced proliferation and enhanced the apoptosis of non-small cell lung cancer by suppressing DNA methylation (40). MTHFD1L supports the Flow of Mitochondrial One-carbon Units into the Methyl Cycle in Embryos as well (22).…”