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METTL3/YTHDF2 m 6A Axis Promotes Tumorigenesis by Degrading SETD7 and KLF4 mRNAs in Bladder Cancer
23 Pages Posted: 1 Aug 2019
More...Abstract
N6-Methyladenosine (m6A) modification, the most prevalent modification of eukaryotic messenger RNA (mRNA), is acknowledged to be involved in the progression of varieties of tumors. However, the specific role of m6A in bladder cancer (BCa) is still poorly understood. In this study, we demonstrated the tumor-promoting function and specific regulatory mechanism of m6A axis, consisting of the core 'writer' METTL3 and the major reader protein YTHDF2. Depletion of METTL3 impaired cancer proliferation and cancer metastasis in vitro and in vivo. Through transcriptome sequencing, m6A methylated RNA immunoprecipitation (MeRIP) and RIP, we identified METTL3/YTHDF2 m6A axis directly degraded mRNAs of tumor suppressors SETD7 and KLF4, contributing to the progression of BCa. In addition, overexpression of SETD7 and KLF4 revealed a consistent phenotype induced by depletion of m6A axis. Thus, our findings of METTL3/YTHDF2/SETD7/KLF4 m6A axis show the insights to the underlying mechanism of carcinogenesis and provide potential therapeutic targets for BCa.
Funding Statement: This work was supported by the National Natural Science Foundation of China [grant numbers 81702500, 81802564, 81874203]; China Postdoctoral Science Foundation Grant [grant number 2018M632489]; Zhejiang Province Medical and Health Scientific Research Project [grant number 2019RC033] and the National key research and development program of China [grant numbers 2017YFC0908002, 2017YFC0908003]. We also appreciated the mRNA-seq work by Ribobio (Guangzhou, China).
Declaration of Interests: The authors declare that there are no conflicts of interest in connection with the work submitted
Ethics Approval Statement: All animals were manipulated according to institutional guidelines and the permission granted by the First Affiliated Hospital, School of Medicine, Zhejiang University.
Keywords: RNA modification; METTL3/YTHDF2 m6A axis; mRNA degradation; Bladder cancer; Carcinogenesis
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