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

研究成果: 雜誌貢獻 › 文章 › 同行評審

104 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
卷	30
發行號	5
DOIs	https://doi.org/10.1016/j.ccell.2016.10.001
出版狀態	已發佈 - 11月 14 2016
對外發佈	是

ASJC Scopus subject areas

腫瘤科
細胞生物學
癌症研究

UN SDG

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10.1016/j.ccell.2016.10.001

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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, 卷 30, 編號 5, 頁 723-736. https://doi.org/10.1016/j.ccell.2016.10.001

@article{20cf4f2df7a84dc085021b762374285e,

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.}",

note = "Funding Information: We thank the Ohio State University Comprehensive Cancer Center microscopy, genomics, nucleic acids, flow cytometry, mass spectrometry, and comparative pathology core facility. We thank Dr. M.-C. Hung, J. Dahlberg, P. Sarnow, A. Deiters, Y. Zheng, C.-S. Chen, and T. Williams for providing reagents; Dr. K. Huebner, W.-L. Shih, and T. Banh for editing; Dr. P. Fadda for NanoString profiling technical support; Dr. S. Palko and Dr. D. Wernicke-Jameson for administrative support. This study was supported by the US NIH (R35CA197706 to C.-M.C.; R01CA193244 to K.G.); Taiwan Ministry of Science and Technology (NSC99-2320-B400-008-MY3 and NSC 99-2628-B002-024-MY3 to C.-M.T.; 101-2917-I-564-052 to H.-L.S.; MOST 105-2632-B-715-001 and MOST 104-2320-B-715-002 to S.-W.W.); Pelotonia Graduate Student Fellowship (to K.-Y.T.); National Key Research & Development Program of China (2016YFA0502204) and National Natural Science Foundation of China (81572739) to (Y.P.); American Cancer Society (IRG-67-003-50) to E.T. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = nov,

day = "14",

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

language = "English",

volume = "30",

pages = "723--736",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

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.

N1 - Funding Information: We thank the Ohio State University Comprehensive Cancer Center microscopy, genomics, nucleic acids, flow cytometry, mass spectrometry, and comparative pathology core facility. We thank Dr. M.-C. Hung, J. Dahlberg, P. Sarnow, A. Deiters, Y. Zheng, C.-S. Chen, and T. Williams for providing reagents; Dr. K. Huebner, W.-L. Shih, and T. Banh for editing; Dr. P. Fadda for NanoString profiling technical support; Dr. S. Palko and Dr. D. Wernicke-Jameson for administrative support. This study was supported by the US NIH (R35CA197706 to C.-M.C.; R01CA193244 to K.G.); Taiwan Ministry of Science and Technology (NSC99-2320-B400-008-MY3 and NSC 99-2628-B002-024-MY3 to C.-M.T.; 101-2917-I-564-052 to H.-L.S.; MOST 105-2632-B-715-001 and MOST 104-2320-B-715-002 to S.-W.W.); Pelotonia Graduate Student Fellowship (to K.-Y.T.); National Key Research & Development Program of China (2016YFA0502204) and National Natural Science Foundation of China (81572739) to (Y.P.); American Cancer Society (IRG-67-003-50) to E.T. Publisher Copyright: © 2016 Elsevier Inc.

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

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UR - http://www.scopus.com/inward/citedby.url?scp=85006515973&partnerID=8YFLogxK

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

摘要

ASJC Scopus subject areas

UN SDG

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