RNA m6A methylation regulates dissemination of cancer cells by modulating expression and membrane localization of ß-catenin.
Mol Ther
; 30(4): 1578-1596, 2022 04 06.
Article
en En
| MEDLINE
| ID: mdl-35033632
ABSTRACT
N6-methyladenosine (m6A) methylation, which is modified by the METTL3/METTL14 complex, is a dominant internal modification in mammalian RNA and tightly linked to cancer progression. Here we reveal that METTL3-promoted cell migration, invasion, and epithelial-to-mesenchymal transition (EMT) are associated with expression and membrane localization of ß-catenin (encoded by CTNNB1), as opposed to Wnt signaling activation in various types of cancer cells, including cervical, lung, and liver cancer. Specifically, METTL3 regulates the transcription, mRNA decay, translation, and subcellular localization of ß-catenin. For CTNNB1 expression, METTL3 indirectly suppresses CTNNB1 transcription by stabilizing its transcription suppressor E2F1 mRNAï¼ deposition of 5'UTR m6A in CTNNB1 promotes its decay in a content-dependent manner via YTHDF2 recognition; 5'UTR m6A in CTNNB1 suppresses its translation efficiency, whereas the global METTL3 level controls the canonical and non-canonical translation of CTNNB1, which is probably associated with the interaction between YTHDF1 and eIF4E1/eIF4E3. For ß-catenin translocation, METTL3 represses membrane localization of ß-catenin and its interaction with E-cadherin by downregulating c-Met kinase, leading to inhibition of cell motility. In vitro, in vivo, and clinical analyses confirm the essential role of ß-catenin and its expression regulators in cancer cell dissemination. The findings not only expand our understanding of m6A modification and its roles in gene expression and subcellular localization of targets but also suggest that the METTL3/ß-catenin axis might be a potential target to inhibit cancer metastasis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Beta Catenina
/
Neoplasias
Límite:
Animals
Idioma:
En
Revista:
Mol Ther
Asunto de la revista:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Año:
2022
Tipo del documento:
Article
País de afiliación:
China