N6-Methyladenosine Methyltransferase METTL14-Mediated Autophagy in Malignant Development of Oral Squamous Cell Carcinoma.

N6-methyladenosine (mA) is the most abundant internal mRNA modification in eukaryotes and is related to stability, localization, or translation efficiency in tumorigenesis. Autophagy plays an important role in the occurrence and development of tumours. However, the relationship between mA and autophagy remains unclear. In this study, we used a rapamycin-induced autophagy model of oral squamous cell carcinoma (OSCC) cells, and observed increased mA RNA methylation. When autophagy was activated, the methyltransferase-like 14 (METTL14) expression was upregulated and influenced the proliferation, migration, and invasiveness of OSCC cells. Through meRIP-seq and RNA-seq analysis, we found that METTL14 directly combined with eukaryotic translation initiation factor gamma 1 (eIF4G1) mRNA and decreased its RNA stability. According to the dual-luciferase reporter and mutagenesis assay, the mutated site 1 of exon 11 of eIF4G1 is the key target of METTL14. Knockdown of the main mA binding protein YTHDF2 may rescue the shortened half-life of mRNA induced by METTL14 overexpression. Furthermore, an tumour xenograft model confirmed that a high METTL14 expression can effectively reduce OSCC growth. Additionally, using clinical samples, we found that patients with advanced or moderately/poorly differentiated tumours exhibited lower METTL14 levels. Taken together, our results revealed that METTL14 mediated eIF4G1 expression mA modification and regulated autophagy levels and biological functions in OSCC. Our findings not only expand our understanding of the correlation between autophagy and RNA methylation in tumorigenesis but also present an opportunity to develop new therapeutic options.