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

ABSTRACT: 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 3METTL3-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.

SUBMITTER: Han H

PROVIDER: S-EPMC8416973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description:Esophageal cancer is a lethal malignancy with high mortality rate, while the molecular mechanisms underlying esophageal cancer pathogenesis are stillis poorly understood. Here we found that the N6-methyladenosine (m6A) methyltransferase METTL3 is significantly up-regulated 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 is essential for 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 in vivo ESCC tumorigenesis in vitro and in vivo. Mechanistically, Mettl3 catalyzed m6A modification promotes NOTCH1 expression and the activation of 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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METTL3 mediated m6A mRNA modification promotes esophageal cancer initiation and progression via Notch signaling pathway

Project description:METTL3 mediated m6A mRNA modification promotes esophageal cancer initiation and progression via Notch signaling pathway

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METTL3-mediated m6A modification of TIMP2 mRNA promotes podocyte injury in diabetic nephropathy.

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METTL3-mediated N6-methyladenosine modification of STAT5A promotes gastric cancer progression by regulating KLF4.

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UBE3A activates the NOTCH pathway and promotes esophageal cancer progression by degradation of ZNF185.

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METTL3-mediated m6A modification of KIF3C-mRNA promotes prostate cancer progression and is negatively regulated by miR-320d.

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