2. Academic Validation
  3. METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N6-methyladenosine-dependent YTHDF binding

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

  • Nat Commun. 2021 Jun 21;12(1):3803. doi: 10.1038/s41467-021-23501-5.
Wei Wang  # 1 2,  Fei Shao  # 3,  Xueying Yang 1,  Juhong Wang 1,  Rongxuan Zhu 1,  Yannan Yang 1,  Gaoxiang Zhao 3,  Dong Guo 4,  Yingli Sun 5,  Jie Wang 2 6,  Qi Xue 1 6,  Shugeng Gao 1 6,  Yibo Gao 7 8,  Jie He 9 10,  Zhimin Lu 11 12 13
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2 Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3 Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, Shandong, China.
  • 4 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.
  • 6 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 7 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. gaoyibo@cicams.ac.cn.
  • 8 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. gaoyibo@cicams.ac.cn.
  • 9 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. prof.hejie@263.net.
  • 10 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. prof.hejie@263.net.
  • 11 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. zhiminlu@zju.edu.cn.
  • 12 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. zhiminlu@zju.edu.cn.
  • 13 Zhejiang University Cancer Center, Hangzhou, China. zhiminlu@zju.edu.cn.
  • # Contributed equally.
PMID: 34155197 DOI: 10.1038/s41467-021-23501-5
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.

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