YY1‐Upregulated MTHFD2 Drives Non‐Small Cell Lung Cancer Progression Through the Regulation of LRRK2

The mitochondrial folate enzyme methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2) has been revealed to extensively participate in the development of non-small cell lung cancer (NSCLC). This study further explored molecular mechanisms which enhance MTHFD2 expression and how MTHFD2 contributes to NSCLC development. Cell growth was evaluated by detecting viability and colony formation potential. Cell apoptosis was detected by flow cytometry. Cell migration and invasion were assessed by transwell and wound-healing assays. Expression analysis was performed by a quantitative PCR, immunoblotting, or immunohistochemistry method. The Yin Yang 1 (YY1)/MTHFD2 relationship was confirmed by luciferase and chromatin immunoprecipitation (ChIP) assays. The MTHFD2/leucine-rich repeat kinase 2 (LRRK2) interaction was tested by co-immunoprecipitation (Co-IP) experiments. MTHFD2 expression was increased in human NSCLC tumors and cell lines. MTHFD2 was identified as a candidate driver in malignant phenotypes of A549 and H322 NSCLC cells in vitro. MTHFD2 depletion suppressed the growth of A549 xenografts in vivo. Mechanistically, YY1 enhanced the transcription of MTHFD2. YY1 elevated MTHFD2 expression to modulate the in vitro phenotypes of A549 and H322 NSCLC cells. Furthermore, MTHFD2 interacted with LRRK2 to regulate LRRK2 expression. MTHFD2 targeted LRRK2 to alter NSCLC cell phenotypes in vitro and growth in vivo. Our findings demonstrate for the first time the protumorigenic role of the YY1/MTHFD2/LRRK2 cascade in NSCLC.