EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis.
Oncotarget
; 8(8): 13509-13520, 2017 Feb 21.
Article
em En
| MEDLINE
| ID: mdl-28088786
ABSTRACT
EZH2 inhibition and reactivation of tumor suppressor microRNAs (miRNAs) represent attractive anti-cancer therapeutic strategies. We found that EZH2-suppressed let 7b and miR-361, two likely tumor suppressors, inhibited endometrial cancer (EC) cell proliferation and invasion, and abrogated cancer stem cell-like properties. In EC cells, EZH2 induced and functioned together with YY1 to epigenetically suppress miR-361, which upregulated Twist, a direct target of miR-361. Treating EC cells with GSK343, a specific EZH2 inhibitor, mimicked the effects of siRNA-mediated EZH2 knockdown, upregulating miR-361 and downregulating Twist expression. Combining GSK343 with 5 AZA-2'-deoxycytidine synergistically suppressed cell proliferation and invasion in vitro, and decreased tumor size and weight in EC cell xenografted mice. Quantitative real-time PCR analysis of 24 primary EC tissues showed that lower let-7b and miR-361 levels were associated with worse patient outcomes. These results were validated in a larger EC patient dataset from The Cancer Genome Atlas. Our findings suggest that EZH2 drives EC progression by regulating miR-361/Twist signaling, and support EZH2 inhibition as a promising anti-EC therapeutic strategy.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piridonas
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Proteínas Nucleares
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Neoplasias do Endométrio
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MicroRNAs
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Inibidores Enzimáticos
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Proteína 1 Relacionada a Twist
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Proteína Potenciadora do Homólogo 2 de Zeste
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Indazóis
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article