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

Wei Wang1,2, Fei Shao3, Xueying Yang1

  • 1Department 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.

Nature Communications
|June 22, 2021
PubMed

Insights

Methyltransferase-like 3 (METTL3) promotes oesophageal squamous cell carcinoma (ESCC) by degrading the APC tumour suppressor. This epitranscriptomic regulation upregulates the Wnt/β-catenin pathway, driving cancer progression and poor prognosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epitranscriptomics

Background:

  • The adenomatous polyposis coli (APC) gene is a crucial tumor suppressor frequently altered in various cancers.
  • The role of epitranscriptomic regulation, specifically N6-methyladenosine (m6A) modification, in controlling APC expression remains largely unexplored.

Purpose of the Study:

  • To investigate the epitranscriptomic regulation of APC in oesophageal squamous cell carcinoma (ESCC).
  • To elucidate the mechanism by which METTL3 influences APC expression and its downstream effects on ESCC development.

Main Methods:

  • Analysis of The Cancer Genome Atlas (TCGA) data from paired ESCC and normal tissues.
  • m6A-RNA immunoprecipitation sequencing (m6A-RIP-seq) to identify m6A-modified targets.
  • Assessment of gene expression, cell proliferation, aerobic glycolysis, and tumor formation in mouse models.

Main Results:

  • METTL3 is significantly upregulated in ESCC tumor tissues compared to adjacent normal tissues.
  • METTL3 enhances m6A modification of APC mRNA, leading to its degradation via YTHDF reader proteins.
  • Reduced APC expression results in increased β-catenin signaling, promoting cyclin D1, c-Myc, and PKM2 expression, thereby enhancing aerobic glycolysis, cell proliferation, and tumor growth.
  • Downregulated APC expression inversely correlates with METTL3 levels in ESCC specimens and predicts poor patient prognosis.

Conclusions:

  • METTL3-mediated m6A modification of APC drives ESCC progression by downregulating APC expression.
  • This mechanism leads to the upregulation of the Wnt/β-catenin pathway, contributing to enhanced tumor growth and poor prognosis in ESCC patients.
  • The METTL3/YTHDF/APC axis represents a potential therapeutic target for ESCC.

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