AUTHOR=Wang Fang , Zhu Yue , Cai Hongshi , Liang Jianfeng , Wang Wenjin , Liao Yan , Zhang Yadong , Wang Cheng , Hou Jinsong 

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

JOURNAL=Frontiers in Oncology

VOLUME=Volume 11 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.738406

DOI=10.3389/fonc.2021.738406

ISSN=2234-943X

ABSTRACT=N6-methyladenosine (m6A) 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 tumors. However, the relationship between m6A and autophagy remains unclear. In this study, we used a rapamycin-induced autophagy model of oral squamous cell carcinoma (OSCC) cells, and observed increased m6A RNA methylation. When autophagy was activated, the expression of methyltransferase-like 14 (METTL14) was upregulated and influenced the proliferation, migration, and invasion 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 downregulated its RNA stability. According to the dual-luciferase reporter and mutagenesis assay, mutated site 1 of exon 11 of eIF4G1 is the key target of METTL14. Knockdown of the main m6A binding protein YTHDF2 may rescue the shortened half-life of eIF4G1 mRNA that was affected by overexpression of METTL14. An in vivo tumor xenograft model confirmed that high METTL14 expression can effectively reduce OSCC growth. Using clinical samples, we found that advanced or moderately/poorly differentiated patients exhibited lower METTL14 levels. Taken together, our results revealed that METTL14 mediated eIF4G1 expression via m6A modification and regulated the autophagy level and biological functions of 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.