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

Fei-Zhou Jiang; Yin-Yan He; Hui-Hui Wang; Hui-Lin Zhang; Jian Zhang; Xiao-Fang Yan; Xiao-Jun Wang; Qi Che; Jie-Qi Ke; Zheng Chen; Huan Tong; Yong-Li Zhang; Fang-Yuan Wang; Yi-Ran Li; Xiao-Ping Wan

doi:10.18632/oncotarget.6350

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

Oncotarget. 2015 Dec 29;6(42):44660-74. doi: 10.18632/oncotarget.6350.

Authors

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, Xiao-Ping Wan^{1

3}

Affiliations

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.

Abstract

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.

Keywords: EZH2; endometrial carcinoma; miR-26a; p53; p68.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Animals
Carcinoma / blood
Carcinoma / enzymology*
Carcinoma / genetics*
Carcinoma / secondary
Cell Line, Tumor
Cell Movement
DEAD-box RNA Helicases / genetics
DEAD-box RNA Helicases / metabolism*
Disease Progression
Endometrial Neoplasms / blood
Endometrial Neoplasms / enzymology*
Endometrial Neoplasms / genetics*
Endometrial Neoplasms / pathology
Enhancer of Zeste Homolog 2 Protein
Epithelial-Mesenchymal Transition*
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
Mice, Nude
MicroRNAs / blood
MicroRNAs / genetics*
Middle Aged
Mutation*
Neoplasm Invasiveness
Polycomb Repressive Complex 2 / genetics
Polycomb Repressive Complex 2 / metabolism*
RNA Processing, Post-Transcriptional
Ribonuclease III / genetics
Ribonuclease III / metabolism*
Signal Transduction
Time Factors
Transfection
Tumor Suppressor Protein p53 / genetics*
Tumor Suppressor Protein p53 / metabolism

Substances

MIRN26A microRNA, human
MicroRNAs
TP53 protein, human
Tumor Suppressor Protein p53
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2
DROSHA protein, human
Ribonuclease III
Ddx5 protein, human
DEAD-box RNA Helicases