METTL3/YTHDF2 m ⁶ A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer

Abstract

N6-Methyladenosine (m⁶ A) modification, the most prevalent modification of eukaryotic messenger RNA (mRNA), is involved in the progression of various tumours. However, the specific role of m⁶ A in bladder cancer (BCa) is still poorly understood. In this study, we demonstrated the tumour-promoting function and specific regulatory mechanism of m⁶ 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, m⁶ A methylated RNA immunoprecipitation (MeRIP) and RIP, we determined that the METTL3/YTHDF2 m⁶ 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 m⁶ A axis. Thus, our findings on the METTL3/YTHDF2/SETD7/KLF4 m⁶ A axis provide the insight into the underlying mechanism of carcinogenesis and highlight potential therapeutic targets for BCa.