Mutant p53 induces EZH2 expression and promotes epithelial–mesenchymal transition by disrupting p68-Drosha complex assembly and attenuating miR-26a processing
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Fei-Zhou Jiang1,*, Yin-Yan He1,*, Hui-Hui Wang2, Hui-Lin Zhang1, Jian Zhang2, Xiao-Fang Yan1, Xiao-Jun Wang1, Qi Che1, Jie-Qi Ke1, Zheng Chen1, Huan Tong1, Yong-Li Zhang1, Fang-Yuan Wang1, Yi-Ran Li1 and Xiao-Ping Wan1,3
1 Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2 Department of Obstetrics and Gynecology, Shanghai Jiaotong University Affiliated International Peace Maternity & Child Health Hospital of the China Welfare Institute, Shanghai, China
3 Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
* These authors have contributed equally to this work
Xiao-Ping Wan, email:
Keywords: endometrial carcinoma, p53, EZH2, p68, miR-26a
Received: May 12, 2015 Accepted: October 14, 2015 Published: November 18, 2015
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.
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