Fine particulate matter induces METTL3-mediated m⁶A modification of BIRC5 mRNA in bladder cancer

Long-term exposure to fine particulate matter (PM_2.5) is reportedly related to a variety of cancers including bladder cancer. However, little is known about the biological mechanism underlying this association. In the present study, PM_2.5 exposure was significantly associated with increased levels of m⁶A modification in bladder cancer patients and bladder cells. METTL3 expression was aberrantly upregulated after PM_2.5 exposure, and METTL3 was involved in PM_2.5-induced m⁶A methylation. Higher METTL3 expression was observed in bladder cancer tissues and METTL3 knockdown dramatically inhibited bladder cancer cell proliferation, colony formation, migration and invasion, inducing apoptosis and disrupting the cell cycle. Mechanistically, PM_2.5 enhanced the expression of METTL3 by inducing the promoter hypomethylation of its promoter and increasing the binding affinity of the transcription factor HIF1A. BIRC5 was identified as the target of METTL3 through m⁶A sequencing (m⁶A-Seq) and KEGG analysis. The methylated BIRC5 transcript was subsequently recognized by IGF2BP3, which increased its mRNA stability. In particular, PM_2.5 exposure promoted the m⁶A modification of BIRC5 and its recognition by IGF2BP3. In addition, BIRC5 was involved in bladder cancer proliferation and metastasis, as well as VEGFA-regulated angiogenesis_. This comprehensive study revealed that PM_2.5 exposure exerts epigenetic regulatory effects on bladder cancer via the HIF1A/METTL3/IGF2BP3/BIRC5/VEGFA network.