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Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a bifunctional enzyme located in the mitochondria. It has been reported to be overexpressed in several malignancies. However, the relationship between the expression of MTHFD2 and non-small cell lung cancer (NSCLC) remains largely unknown. In this study, we found that MTHFD2 was significantly overexpressed in NSCLC tissues and cell lines. Knockdown of MTHFD2 resulted in reduced cell growth and tumorigenicity in vitro and in vivo. Besides, the mRNA and protein expression level of cell cycle genes, such as CCNA2, MCM7 and SKP2, was decreased in MTHFD2 knockdown H1299 cells. Our results indicate that the inhibitory effect of MTHFD2 knockdown on NSCLC may be mediated via suppressing cell cycle-related genes. These findings delineate the role of MTHFD2 in the development of NSCLC and may have potential applications in the treatment of NSCLC. K E Y W O R D S bioinformatics, cell cycle, methylenetetrahydrofolate dehydrogenase 2, non-small cell lung cancer | 1569 YU et al. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Yu C, Yang L, Cai M, et al. Downregulation of MTHFD2 inhibits NSCLC progression by suppressing cycle-related genes. J Cell Mol Med.

The ubiquitin‐proteasome system, which is one of the systems for cell protein homeostasis and degradation, happens through the ordered and coordinated action of three types of enzymes, E1 ubiquitin‐activating enzyme, E2 ubiquitin‐carrier enzyme, E3 ubiquitin‐protein ligase. Tripartite motif‐containing (TRIM) family proteins are the richest subfamily of really interesting new gene E3 ubiquitin ligases, which play a critical role not only in many biological processes, including proliferation, apoptosis, pyroptosis, innate immunity, and autophagy, but also many diseases like cancer, diabetes mellitus, and neurodegenerative disease. Increasing evidence suggests that TRIM family proteins play a vital role in modulating autophagy, pyroptosis, and diabetes mellitus. The aim of this review is to discuss the role of TRIM proteins in the regulation of autophagy, pyroptosis, diabetes mellitus, and diabetic complications.

Carboxypeptidase A4 (CPA4) is a member of the metallocarboxypeptidase family. A previous study indicated that CPA4 may participate in the modulation of peptide hormone activity and hormone‐regulated tissue growth and differentiation. However, the role of CPA4 in lung tumorigenesis remains unclear. Our study revealed that CPA4 expression was higher in both lung cancer cells and tumor tissues. We performed 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assays, colony‐formation assays, and Cellomics ArrayScan Infinity analysis to demonstrate that CPA4 knockdown inhibited non small–cell lung cancer (NSCLC) cell proliferation. Conversely, ectopic expression of CPA4 enhanced lung cancer cell proliferation. Consistent with these observations, we generated xenograft tumor models to confirm that CPA4 downregulation suppressed NSCLC cell growth. Mechanistically, we revealed that CPA4 downregulation may induce apoptosis and G1‐S arrest by suppressing the protein kinase B/c‐MYC pathway. These results suggest that CPA4 has an oncogenic effect on lung cancer growth. Taken together, we identified a novel gene in lung cancer that might provide a basis for new therapeutic targets.

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