Cancer-associated fibroblasts-secreted lactate promotes RNA polymerase III subunit G-mediated epithelial-mesenchymal transition in non-small cell lung cancer by increasing m6A modification of zinc finger protein 384.

Most advanced non-small cell lung cancer (NSCLC) patients have metastasis, which poses great risks to their survival. As the most abundant components in the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) can induce epithelial-mesenchymal transition (EMT) to promote tumor. This study aimed to explore the potential molecular mechanisms of CAFs-mediated EMT in NSCLC. The gene expression was assessed using RT-qPCR, immunofluorescence, and Western Blot. Cells phenotypes were evaluated through CCK-8, scratch, and transwell assays, respectively. Lactate levels were measured with a commercial kit. The m6A level of zinc finger protein 384 (ZNF384) was measured using methylated RNA immunoprecipitation. The molecular interactions was checked using chromatin immunoprecipitation and dual luciferase reporter assay. ZNF384 was upregulated in NSCLC. ZNF384 knockdown suppressed NSCLC cell proliferation and inhibited EMT-related protein vimentin and Snail, but elevated E-Cadherin. Mechanistically, CAFs-secreted lactate promoted the H3K18 lactylation of methyltransferase-like 3 (METTL3) promoter region and further increased the m6A modification of ZNF384. ZNF384 promoted the transcription of RNA polymerase III subunit G (POLR3G) by binding to POLR3G promoter region. CAFs induced EMT in NSCLC cells by enhancing ZNF384 expression. Additionally, POLRG3 silencing counteracted the promoting effect of ZNF384 overexpression on EMT in NSCLC. CAFs facilitating cell proliferation and EMT by modulating the METTL3/ZNF384/POLR3G axis. It is suggested that CAFS-related TME could be an approach for treating NSCLC.