N <sup>6</sup>-Methyladenosine METTL3 Facilitates Oral Squamous Cell Carcinoma Tumorigenesis via YTHDF1-Dependent c-Myc Translation

Abstract

N6-Methyladenosine (m6A) is the most common internal modification of eukaryotic messenger RNA (mRNA) occured on the N6 nitrogen of adenosine. However, the roles of m6A in oral squamous cell carcinoma (OSCC) are still elusive. Here, we investigate the function and mechanism of methyltransferase like 3 (METTL3) in the OSCC tumorigenesis. Clinically, METTL3 was significantly up-regulated in tissue samples and correlated with the poor prognosis of OSCC patients. Functionally, loss and gain studies illustrated that METTL3 promoted the proliferation, invasion and migration of OSCC cells in vitro, and the METTL3 knockdown inhibited the tumor growth in vivo. Mechanically, MeRIP-Seq analysis and mechanical investigation indicated METTL3 targeted the 3'-UTR (near to stop codon) of c-Myc transcript to install the m6A modification, thereby enhancing its translation. Furthermore, exploration confirmed that YTHDF1 mediated the m6A-increased translation of c-Myc mRNA catalyzed by METTL3. In conclusion, our findings herein identify that METTL3 accelerates the c-Myc translation via YTHDF1-mediated m6A modification, thereby giving rise to OSCC tumorigenesis. Funding Statement: This work was supported by National Natural Science Foundation of China (Grant/Award Numbers: 81701019, 81870763). Tianjin Science and Technology Commission General Project (Grant/Award Numbers: 18JCYBJC92400). Declaration of Interests: All authors declare no conflicts of interest. Ethics Approval Statement: The processes were performed according to the principles of the Declaration of Helsinki. The clinical human research had been approved by Institutional Ethics Committee of The Hospital of Stomatology Tianjin Medical University.