N6-methyladenosine demethyltransferase FTO-mediated autophagy in malignant development of oral squamous cell carcinoma

• Published in: Oncogene 2021-06, Vol.40 (22), p.3885-3898
• Main Authors: Wang, Fang, Liao, Yan, Zhang, Ming, Zhu, Yue, Wang, Wenjin, Cai, Hongshi, Liang, Jianfeng, Song, Fan, Hou, Chen, Huang, Shuojin, Zhang, Yadong, Wang, Cheng, Hou, Jinsong
• Format: Article
• Language: English
• Subjects: 101/28; 13; 13/89; 42; 42/109; 42/35; 631/67/1059/153; 631/67/1665; 82; 82/1; 82/51; Adenosine - analogs & derivatives; Adenosine - metabolism; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - metabolism; Animals; Apoptosis; Autophagy; Autophagy (Cytology); Autophagy - physiology; Body fat; Cancer; Cell Biology; Cell Line, Tumor; Development and progression; Eukaryotic Initiation Factor-4G - metabolism; Female; Gene expression; Genetic aspects; Genetic transcription; Head and Neck Neoplasms - enzymology; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Health aspects; Heterografts; Human Genetics; Humans; Initiation factor eIF-4G; Internal Medicine; Medicine; Medicine & Public Health; Methyltransferases; Mice; Mice, Inbred NOD; Mice, SCID; Mouth cancer; Mutagenesis; N6-methyladenosine; Oncology; Oncology, Experimental; Oral cancer; Oral squamous cell carcinoma; Phagocytosis; Proteins; Rapamycin; RNA modification; RNA-binding protein; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - enzymology; Squamous Cell Carcinoma of Head and Neck - genetics; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - pathology; Survival Rate; Tumorigenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-01820-7

N6-methyladenosine (m 6 A) is the most abundant internal mRNA modification in eukaryotes and plays an important role in tumorigenesis. However, the underlying mechanism remains largely unclear. Here, we established a cell model of rapamycin-induced autophagy to screen m 6 A-modifying enzymes. We found that m 6 A demethylase fat mass and obesity-associated protein (FTO) plays a key role in regulating autophagy and tumorigenesis by targeting the gene encoding eukaryotic translation initiation factor gamma 1 ( eIF4G1 ) in oral squamous cell carcinoma (OSCC). Knocked down of FTO expression in OSCC cell lines, resulting in downregulation of eIF4G1 along with enhanced autophagic flux and inhibition of tumorigenesis. Rapamycin inhibited FTO activity, and directly targeted eIF4G1 transcripts and mediated their expression in an m 6 A-dependent manner. Dual-luciferase reporter and mutagenesis assays confirmed that YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2) targets eIF4G1 . Conclusively, after FTO silencing, YTHDF2 captured eIF4G1 transcripts containing m 6 A, resulting in mRNA degradation and decreased expression of eIF4G1 protein, thereby promoting autophagy and reducing tumor occurrence. Therefore, rapamycin may regulate m 6 A levels, determining the autophagic flux of OSCC, thereby affecting the biological characteristics of cancer cells. This insight expands our understanding of the crosstalk between autophagy and RNA methylation in tumorigenesis, which is essential for therapeutic strategy development for OSCC.