EZH2 cooperates with gain-of-function p53 mutants to promote cancer growth and metastasis.
EMBO J
; 38(5)2019 03 01.
Article
en En
| MEDLINE
| ID: mdl-30723117
ABSTRACT
In light of the increasing number of identified cancer-driven gain-of-function (GOF) mutants of p53, it is important to define a common mechanism to systematically target several mutants, rather than developing strategies tailored to inhibit each mutant individually. Here, using RNA immunoprecipitation-sequencing (RIP-seq), we identified the Polycomb-group histone methyltransferase EZH2 as a p53 mRNA-binding protein. EZH2 bound to an internal ribosome entry site (IRES) in the 5'UTR of p53 mRNA and enhanced p53 protein translation in a methyltransferase-independent manner. EZH2 augmented p53 GOF mutant-mediated cancer growth and metastasis by increasing protein levels of mutant p53. EZH2 overexpression was associated with worsened outcome selectively in patients with p53-mutated cancer. Depletion of EZH2 by antisense oligonucleotides inhibited p53 GOF mutant-mediated cancer growth. Our findings reveal a non-methyltransferase function of EZH2 that controls protein translation of p53 GOF mutants, inhibition of which causes synthetic lethality in cancer cells expressing p53 GOF mutants.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Próstata
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ARN Mensajero
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Regulación Neoplásica de la Expresión Génica
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Proteína p53 Supresora de Tumor
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Proteína Potenciadora del Homólogo Zeste 2
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Mutación con Ganancia de Función
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
EMBO J
Año:
2019
Tipo del documento:
Article