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

Oncogene volume 40, pages 3885–3898 (2021)Cite this article

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Abstract

N6-methyladenosine (m6A) 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 m6A-modifying enzymes. We found that m6A 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 m6A-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 m6A, resulting in mRNA degradation and decreased expression of eIF4G1 protein, thereby promoting autophagy and reducing tumor occurrence. Therefore, rapamycin may regulate m6A 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.

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Fig. 1: FTO expression is elevated in OSCC tissues and inhibited by rapamycin.
Fig. 2: Downregulation of FTO enhances the autophagic flux and decreases the proliferation, migration, and invasion of OSCC cells.
Fig. 3: eIF4G1 is involved in m6A-regulated autophagy in cancer cells.
Fig. 4: Downregulation of eIF4G1 expression enhances autophagic flux and decreases the proliferation, migration, and invasion of OSCC cells.
Fig. 5: Correlation of the expression levels of FTO and eIF4G1 in vivo.
Fig. 6: A proposed model for the critical link between FTO and autophagy in rapamycin-treated OSCC cells.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81874128 and 82072994); Sun Yat-sen University Clinical Research 5010 Program (Grant No. 2015018).

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  1. These authors contributed equally: Fang Wang, Yan Liao, Ming Zhang

Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

    Fang Wang, Yan Liao, Ming Zhang, Yue Zhu, Wenjin Wang, Hongshi Cai, Jianfeng Liang, Fan Song, Chen Hou, Shuojin Huang, Yadong Zhang, Cheng Wang & Jinsong Hou

  2. Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China

    Fang Wang, Yan Liao, Ming Zhang, Yue Zhu, Wenjin Wang, Hongshi Cai, Jianfeng Liang, Fan Song, Chen Hou, Shuojin Huang, Yadong Zhang, Cheng Wang & Jinsong Hou

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Wang, F., Liao, Y., Zhang, M. et al. N6-methyladenosine demethyltransferase FTO-mediated autophagy in malignant development of oral squamous cell carcinoma. Oncogene 40, 3885–3898 (2021). https://doi.org/10.1038/s41388-021-01820-7

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