ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5

Hui Lung Sun, Ri Cui, Jian Kang Zhou, Kun yu Teng, Yung Hsuan Hsiao, Kotaro Nakanishi, Matteo Fassan, Zhenghua Luo, Guqin Shi, Esmerina Tili, Huban Kutay, Francesca Lovat, Caterina Vicentini, Han Li Huang, Shih Wei Wang, Taewan Kim, Nicola Zanesi, Young Jun Jeon, Tae Jin Lee, Jih Hwa GuhMien Chie Hung, Kalpana Ghoshal, Che Ming Teng, Yong Peng, Carlo M. Croce

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70 引文 斯高帕斯(Scopus)

摘要

MicroRNAs (miRNA) are mostly downregulated in cancer. However, the mechanism underlying this phenomenon and the precise consequence in tumorigenesis remain obscure. Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. In liver cancer, the ERK-mediated XPO5 suppression reduces miR-122, increases microtubule dynamics, and results in tumor development and drug resistance. Analysis of clinical specimens further showed that XPO5 phosphorylation is associated with poor prognosis for liver cancer patients. Our study reveals a function of ERK in miRNA biogenesis and suggests that modulation of miRNA export has potential clinical implications.

原文英語
頁(從 - 到)723-736
頁數14
期刊Cancer Cell
30
發行號5
DOIs
出版狀態已發佈 - 十一月 14 2016

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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