METTL3/YTHDF2 m6A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer

N6-Methyladenosine (m(6)A) modification, the most prevalent modification of eukaryotic messenger RNA (mRNA), is involved in the progression of various tumours. However, the specific role of m(6)A in bladder cancer (BCa) is still poorly understood. In this study, we demonstrated the tumour-promoting function and specific regulatory mechanism of m(6)A axis, consisting of the core 'writer' protein METTL3 and the major reader protein YTHDF2. Depletion of METTL3 impaired cancer proliferation and cancer metastasis in vitro and in vivo. Through transcriptome sequencing, m(6)A methylated RNA immunoprecipitation (MeRIP) and RIP, we determined that the METTL3/YTHDF2 m(6)A axis directly degraded the mRNAs of the tumour suppressors SETD7 and KLF4, contributing to the progression of BCa. In addition, overexpression of SETD7 and KLF4 revealed a phenotype consistent with that induced by depletion of the m(6)A axis. Thus, our findings on the METTL3/YTHDF2/SETD7/KLF4 m(6)A axis provide the insight into the underlying mechanism of carcinogenesis and highlight potential therapeutic targets for BCa.