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

Wei Wang, Fei Shao, Xueying Yang, Juhong Wang, Rongxuan Zhu, Yannan Yang, Gaoxiang Zhao, Dong Guo, Yingli Sun, Jie Wang, Qi Xue, Shugeng Gao, Yibo Gao (), Jie He () and Zhimin Lu ()
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Wei Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Fei Shao: Affiliated Hospital of Qingdao University and Qingdao Cancer Institute
Xueying Yang: Chinese Academy of Medical Sciences and Peking Union Medical College
Juhong Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Rongxuan Zhu: Chinese Academy of Medical Sciences and Peking Union Medical College
Yannan Yang: Chinese Academy of Medical Sciences and Peking Union Medical College
Gaoxiang Zhao: Affiliated Hospital of Qingdao University and Qingdao Cancer Institute
Dong Guo: The First Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine
Yingli Sun: Chinese Academy of Medical Sciences and Peking Union Medical College
Jie Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Qi Xue: Chinese Academy of Medical Sciences and Peking Union Medical College
Shugeng Gao: Chinese Academy of Medical Sciences and Peking Union Medical College
Yibo Gao: Chinese Academy of Medical Sciences and Peking Union Medical College
Jie He: Chinese Academy of Medical Sciences and Peking Union Medical College
Zhimin Lu: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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. m6A-RNA immunoprecipitation sequencing revealed that METTL3 upregulates the m6A 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.

Date: 2021
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DOI: 10.1038/s41467-021-23501-5

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