Cigarette smoking, by accelerating the cell cycle, promotes the progression of non-small cell lung cancer through an HIF-1α-METTL3-m6A/CDK2AP2 axis

Cigarette smoking killed about 8 million people every year and promoted non-small cell lung cancer (NSCLC). We investigated the molecular mechanism of smoking-promoted NSCLC progression. Relative to non-smokers, NSCLC patients who were smokers had a higher tumor malignancy. For NSCLC cells, cigarette smoke extract (CSE) increased levels of HIF-1α, METTL3, Cyclin E1, and CDK2 and promoted the G1/S transition, which promoted cell proliferation. Down-regulation HIF-1α or METTL3 reversed these effects. meRIP-seq and RNA-seq revealed the m6A modification in Cyclin Dependent Kinase 2 Associated Protein 2 (CDK2AP2) mRNA as the key downstream target. Further, for NSCLC cells exposed to CSE, HIF-1α activated METTL3 transcription. Xenografts in nude mice demonstrated that HIF-1α via METTL3 participated in tumor growth. In NSCLC tissues of smokers, protein levels of HIF-1α and METTL3 were higher, and levels of CDK2AP2 were lower. In conclusion, HIF-1α via METTL3 regulation of the m6A modification of CDK2AP2 mRNA drives smoking-induced progression of NSCLC through promoting cell proliferation. This is a previously unknown molecular mechanism for smoking-induced NSCLC progression. The results have potential value for treatment of NSCLC, especially for patients who smoke.