METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N6-methyladenosine-dependent YTHDF binding

• Published in: Nature communications 2021-06, Vol.12 (1), p.3803-3803, Article 3803
• Main Authors: Wang, Wei, Shao, Fei, Yang, Xueying, Wang, Juhong, Zhu, Rongxuan, Yang, Yannan, Zhao, Gaoxiang, Guo, Dong, Sun, Yingli, Wang, Jie, Xue, Qi, Gao, Shugeng, Gao, Yibo, He, Jie, Lu, Zhimin
• Format: Article
• Language: English
• Subjects: 13; 38; 42; 49; 631/337; 631/67; 631/80; 692/308; 692/4020; Adenomatous polyposis coli; c-Myc protein; Cancer; Cell proliferation; Cyclin D1; Degradation; DNA methylation; Esophagus; Gene expression; Gene sequencing; Glycolysis; Humanities and Social Sciences; Immunoprecipitation; Methyltransferase; mRNA; multidisciplinary; Myc protein; N6-methyladenosine; Polyposis coli; Science; Science (multidisciplinary); Squamous cell carcinoma; Tumor suppressor genes; Tumors; Wnt protein; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23501-5

The adenomatous polyposis coli ( APC ) is a frequently mutated tumour suppressor gene in cancers. However, whether APC is regulated at the epitranscriptomic level remains elusive. In this study, we analysed TCGA data and separated 200 paired oesophageal squamous cell carcinoma (ESCC) specimens and their adjacent normal tissues and demonstrated that methyltransferase-like 3 (METTL3) is highly expressed in tumour tissues. m 6 A-RNA immunoprecipitation sequencing revealed that METTL3 upregulates the m 6 A modification of APC , which recruits YTHDF for APC mRNA degradation. Reduced APC expression increases the expression of β-catenin and β-catenin-mediated cyclin D1, c-Myc, and PKM2 expression, thereby leading to enhanced aerobic glycolysis, ESCC cell proliferation, and tumour formation in mice. In addition, downregulated APC expression correlates with upregulated METTL3 expression in human ESCC specimens and poor prognosis in ESCC patients. Our findings reveal a mechanism by which the Wnt/β-catenin pathway is upregulated in ESCC via METTL3/YTHDF-coupled epitranscriptomal downregulation of APC . The epitranscriptomic regulation of adenomatous polyposis coli (APC) tumour suppressor gene in cancers is unclear. Here the authors show that N6-methyladenosine methylation writer METTL3 downregulates APC by recruiting YTHDF2 for APC mRNA degradation, and that this promotes glycolysis and tumour growth in oesophageal cancers.