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

Author

Listed:
  • Wei Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    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
    Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Qi Xue

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Shugeng Gao

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yibo Gao

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Jie He

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Zhimin Lu

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    The First Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine
    Zhejiang University Cancer Center)

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.

Suggested Citation

  • 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 & Zhimin Lu, 2021. "METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N6-methyladenosine-dependent YTHDF binding," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23501-5
    DOI: 10.1038/s41467-021-23501-5
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    Cited by:

    1. Yaodong Zhang & Zijian Ma & Changxian Li & Cheng Wang & Wangjie Jiang & Jiang Chang & Sheng Han & Zefa Lu & Zicheng Shao & Yirui Wang & Hongwei Wang & Chenyu Jiao & Dong Wang & Xiaofeng Wu & Hongbing , 2022. "The genomic landscape of cholangiocarcinoma reveals the disruption of post-transcriptional modifiers," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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