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

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 (mA) 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 and . We further established ESCC initiation and progression models using conditional knockout mouse and revealed that 3METTL3-mediated mA modification promotes ESCC initiation and progression . Moreover, using METTL3 overexpression ESCC cell model and conditional knockin mouse model, we demonstrated the critical function of METTL3 in promoting ESCC tumorigenesis and . Mechanistically, METTL3-catalyzed mA 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.