Simvastatin is beneficial to lung cancer progression by inducing METTL3-induced m6A modification on EZH2 mRNAe

OBJECTIVE: To elucidate the molecular mechanism of Simvastatin on inhibiting malignant progression of lung cancer. PATIENTS AND METHODS: Relative levels of METTL3 and EZH2 in lung cancer tissues and adjacent normal ones were detected by quantitative real-time polymerase chain reaction (qRT-PCR). In addition, their levels in lung cancer patients with different pathological stages were determined as well. A549 cells were induced with different doses of Simvastatin for 24 h. Subsequently, relative levels of METTL3 and EZH2 in cells were detected. Proliferative and metastatic abilities in A549 cells were examined by cell counting kit-8 (CCK-8), 5-Ethynyl-2'- deoxyuridine (EdU) and transwell assay, respectively. RIP assay was conducted to detect the presence of m6A modification on EZH2 mRNA and the interaction between IGF2BP2 and EZH2. Relative levels of EZH2 and epithelial-mesenchymal transition (EMT)-associated genes (E-cadherin and N-cadherin), and metastatic abilities were detected in Simvastatin-induced A549 cells transfected with pcDNA-METTL3. RESULTS: METTL3 and EZH2 levels were upregulated in lung cancer tissues, which were higher in advanced stage lung cancer patients. Their levels, as well as cell proliferative and metastatic abilities, were dose-dependently inhibited in Simvastatin-induced A549 cells. METTL3 positively regulated EZH2 level, and m6A modification on its mRNA. Moreover, the interaction between IGF2BP2 and EZH2 could be inhibited by knockdown of METTL3. Simvastatin could abolish the role of METTL3 in regulating relative levels of EZH2 and EMT-associated genes, as well as metastatic abilities in A549 cells. CONCLUSIONS: Simvastatin induces METTL3 down-regulation in lung cancer tissues, which further influences EMT via m6A modification on EZH2 mRNA and thus inhibits the malignant progression of lung cancer.