Molecular Therapy: Nucleic Acids (Dec 2021)

METTL3-mediated m6A mRNA modification promotes esophageal cancer initiation and progression via Notch signaling pathway

  • Hui Han,
  • Chunlong Yang,
  • Shuishen Zhang,
  • Maosheng Cheng,
  • Siyao Guo,
  • Yan Zhu,
  • Jieyi Ma,
  • Yu Liang,
  • Lu Wang,
  • Siyi Zheng,
  • Zhaoyu Wang,
  • Demeng Chen,
  • Yi-Zhou Jiang,
  • Shuibin Lin

Journal volume & issue
Vol. 26
pp. 333 – 346

Abstract

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Esophageal cancer is a lethal malignancy with a high mortality rate, while the molecular mechanisms underlying esophageal cancer pathogenesis are still poorly understood. Here, we found that the N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) is significantly upregulated in esophageal squamous cell carcinoma (ESCC) and associated with poor patient prognosis. Depletion of METTL3 results in decreased ESCC growth and progression in vitro and in vivo. We further established ESCC initiation and progression models using Mettl3 conditional knockout mouse and revealed that METTL3-mediated m6A modification promotes ESCC initiation and progression in vivo. Moreover, using METTL3 overexpression ESCC cell model and Mettl3 conditional knockin mouse model, we demonstrated the critical function of METTL3 in promoting ESCC tumorigenesis in vitro and in vivo. Mechanistically, METTL3-catalyzed m6A modification promotes NOTCH1 expression and the activation of the Notch signaling pathway. Forced activation of Notch signaling pathway successfully rescues the growth, migration, and invasion capacities of METTL3-depleted ESCC cells. Our data uncovered important mechanistical insights underlying ESCC tumorigenesis and provided molecular basis for the development of novel strategies for ESCC diagnosis and treatment.

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