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

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)723-736
Number of pages14
JournalCancer Cell
Volume30
Issue number5
DOIs
Publication statusPublished - Nov 14 2016

Fingerprint

Karyopherins
MicroRNAs
Down-Regulation
Phosphorylation
Liver Neoplasms
Peptidylprolyl Isomerase
Drug Resistance
Microtubules
Neoplasms
Carcinogenesis

Keywords

  • drug resistance
  • ERK
  • Exportin-5
  • global downregulation
  • liver cancer
  • microtubule
  • miR-122
  • miRNA
  • nuclear export
  • Pin1

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Sun, H. L., Cui, R., Zhou, J. K., Teng, K. Y., Hsiao, Y. H., Nakanishi, K., ... Croce, C. M. (2016). ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5. Cancer Cell, 30(5), 723-736. https://doi.org/10.1016/j.ccell.2016.10.001

ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5. / Sun, Hui Lung; Cui, Ri; Zhou, Jian Kang; Teng, Kun yu; Hsiao, Yung Hsuan; Nakanishi, Kotaro; Fassan, Matteo; Luo, Zhenghua; Shi, Guqin; Tili, Esmerina; Kutay, Huban; Lovat, Francesca; Vicentini, Caterina; Huang, Han Li; Wang, Shih Wei; Kim, Taewan; Zanesi, Nicola; Jeon, Young Jun; Lee, Tae Jin; Guh, Jih Hwa; Hung, Mien Chie; Ghoshal, Kalpana; Teng, Che Ming; Peng, Yong; Croce, Carlo M.

In: Cancer Cell, Vol. 30, No. 5, 14.11.2016, p. 723-736.

Research output: Contribution to journalArticle

Sun, HL, Cui, R, Zhou, JK, Teng, KY, Hsiao, YH, Nakanishi, K, Fassan, M, Luo, Z, Shi, G, Tili, E, Kutay, H, Lovat, F, Vicentini, C, Huang, HL, Wang, SW, Kim, T, Zanesi, N, Jeon, YJ, Lee, TJ, Guh, JH, Hung, MC, Ghoshal, K, Teng, CM, Peng, Y & Croce, CM 2016, 'ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5', Cancer Cell, vol. 30, no. 5, pp. 723-736. https://doi.org/10.1016/j.ccell.2016.10.001
Sun HL, Cui R, Zhou JK, Teng KY, Hsiao YH, Nakanishi K et al. ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5. Cancer Cell. 2016 Nov 14;30(5):723-736. https://doi.org/10.1016/j.ccell.2016.10.001
Sun, Hui Lung ; Cui, Ri ; Zhou, Jian Kang ; Teng, Kun yu ; Hsiao, Yung Hsuan ; Nakanishi, Kotaro ; Fassan, Matteo ; Luo, Zhenghua ; Shi, Guqin ; Tili, Esmerina ; Kutay, Huban ; Lovat, Francesca ; Vicentini, Caterina ; Huang, Han Li ; Wang, Shih Wei ; Kim, Taewan ; Zanesi, Nicola ; Jeon, Young Jun ; Lee, Tae Jin ; Guh, Jih Hwa ; Hung, Mien Chie ; Ghoshal, Kalpana ; Teng, Che Ming ; Peng, Yong ; Croce, Carlo M. / ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5. In: Cancer Cell. 2016 ; Vol. 30, No. 5. pp. 723-736.
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