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Mutant p53 induces EZH2 expression and promotes epithelial–mesenchymal transition by disrupting p68-Drosha complex assembly and attenuating miR-26a processing

The tumor suppressor p53 and the transcriptional repressor Enhancer of Zeste Homolog 2 (EZH2) have both been implicated in the regulation of epithelial-mesenchymal transition (EMT) and tumor metastasis via their impacts on microRNA expression. Here, we report that mutant p53 (mutp53) promotes EMT in...

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Detalles Bibliográficos
Autores principales: Jiang, Fei-Zhou, He, Yin-Yan, Wang, Hui-Hui, Zhang, Hui-Lin, Zhang, Jian, Yan, Xiao-Fang, Wang, Xiao-Jun, Che, Qi, Ke, Jie-Qi, Chen, Zheng, Tong, Huan, Zhang, Yong-Li, Wang, Fang-Yuan, Li, Yi-Ran, Wan, Xiao-Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792583/
https://www.ncbi.nlm.nih.gov/pubmed/26587974
Descripción
Sumario:The tumor suppressor p53 and the transcriptional repressor Enhancer of Zeste Homolog 2 (EZH2) have both been implicated in the regulation of epithelial-mesenchymal transition (EMT) and tumor metastasis via their impacts on microRNA expression. Here, we report that mutant p53 (mutp53) promotes EMT in endometrial carcinoma (EC) by disrupting p68-Drosha complex assembly. Overexpression of mutp53 has the opposite effect of wild-type p53 (WTp53), repressing miR-26a expression by reducing pri-miR-26a-1 processing in p53-null EC cells. Re-expression of miR-26a in mutp53 EC cells decreases cell invasion and promotes mesenchymal-epithelial transition (MET). Rescuing miR-26a expression also inhibits EZH2, N-cadherin, Vimentin, and Snail expression and induces E-cadherin expression both in vitro and in vivo. Moreover, patients with higher serum miR-26a levels have a better survival rate. These results suggest that p53 gain-of-function mutations accelerate EC tumor progression and metastasis by interfering with Drosha and p68 binding and pri-miR-26a-1 processing, resulting in reduced miR-26a expression and EZH2 overexpression.