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 Guh; Mien Chie Hung; Kalpana Ghoshal; Che Ming Teng; Yong Peng; Carlo M. Croce

doi:10.1016/j.ccell.2016.10.001

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 Guh

Mien Chie Hung, Kalpana Ghoshal, Che Ming Teng, Yong Peng, Carlo M. Croce

Ph.D. Program in Drug Discovery and Development Industry

Research output: Contribution to journal › Article › peer-review

131 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 language	English
Pages (from-to)	723-736
Number of pages	14
Journal	Cancer Cell
Volume	30
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2016.10.001
Publication status	Published - Nov 14 2016

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2016.10.001

Cite this

Sun, H. L., Cui, R., Zhou, J. K., Teng, K. Y., Hsiao, Y. H., Nakanishi, K., Fassan, M., Luo, Z., Shi, G., Tili, E., Kutay, H., Lovat, F., Vicentini, C., Huang, H. L., Wang, S. W., Kim, T., Zanesi, N., Jeon, Y. J., Lee, T. J., ... 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

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

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title = "ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5",

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.",

keywords = "ERK, Exportin-5, Pin1, drug resistance, global downregulation, liver cancer, miR-122, miRNA, microtubule, nuclear export",

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

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year = "2016",

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doi = "10.1016/j.ccell.2016.10.001",

language = "English",

volume = "30",

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journal = "Cancer Cell",

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T1 - ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5

AU - Sun, Hui Lung

AU - Cui, Ri

AU - Zhou, Jian Kang

AU - Teng, Kun yu

AU - Hsiao, Yung Hsuan

AU - Nakanishi, Kotaro

AU - Fassan, Matteo

AU - Luo, Zhenghua

AU - Shi, Guqin

AU - Tili, Esmerina

AU - Kutay, Huban

AU - Lovat, Francesca

AU - Vicentini, Caterina

AU - Huang, Han Li

AU - Wang, Shih Wei

AU - Kim, Taewan

AU - Zanesi, Nicola

AU - Jeon, Young Jun

AU - Lee, Tae Jin

AU - Guh, Jih Hwa

AU - Hung, Mien Chie

AU - Ghoshal, Kalpana

AU - Teng, Che Ming

AU - Peng, Yong

AU - Croce, Carlo M.

PY - 2016/11/14

Y1 - 2016/11/14

N2 - 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.

AB - 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.

KW - ERK

KW - Exportin-5

KW - Pin1

KW - drug resistance

KW - global downregulation

KW - liver cancer

KW - miR-122

KW - miRNA

KW - microtubule

KW - nuclear export

UR - https://www.scopus.com/pages/publications/85006515973

UR - https://www.scopus.com/pages/publications/85006515973#tab=citedBy

U2 - 10.1016/j.ccell.2016.10.001

DO - 10.1016/j.ccell.2016.10.001

M3 - Article

C2 - 27846390

AN - SCOPUS:85006515973

SN - 1535-6108

VL - 30

SP - 723

EP - 736

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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