ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5

Hui-Lung Sun; Ri Cui; JianKang 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

Cancer Cell. 2016 Nov 14;30(5):723-736. doi: 10.1016/j.ccell.2016.10.001.

Authors

Hui-Lung Sun¹, Ri Cui², JianKang Zhou³, Kun-Yu Teng⁴, Yung-Hsuan Hsiao⁵, Kotaro Nakanishi⁶, Matteo Fassan⁷, Zhenghua Luo², Guqin Shi⁸, Esmerina Tili⁹, Huban Kutay⁴, Francesca Lovat², Caterina Vicentini¹⁰, Han-Li Huang¹¹, Shih-Wei Wang¹², Taewan Kim¹³, Nicola Zanesi², Young-Jun Jeon², Tae Jin Lee², Jih-Hwa Guh¹⁴, Mien-Chie Hung¹⁵, Kalpana Ghoshal⁴, Che-Ming Teng¹⁶, Yong Peng¹⁷, Carlo M Croce¹⁸

Affiliations

¹ Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA; Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
² Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA.
³ Department of Thoracic Surgery, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
⁴ Department of Pathology, Ohio State University, Columbus, OH 43210, USA.
⁵ Department of Human Sciences, Human Nutrition Program, College of Education and Human Ecology, Ohio State University, Columbus, OH 43210, USA.
⁶ Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH 43210, USA.
⁷ Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA; ARC-NET Research Centre, University and Hospital Trust of Verona, Verona 37126, Italy.
⁸ Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
⁹ Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA; Department of Anesthesiology, Ohio State University, Columbus, OH 43210, USA.
¹⁰ ARC-NET Research Centre, University and Hospital Trust of Verona, Verona 37126, Italy.
¹¹ The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
¹² Department of Medicine, Mackay Medical College, New Taipei City 25245, Taiwan.
¹³ Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁴ School of Pharmacy, National Taiwan University, Taipei 10051, Taiwan.
¹⁵ Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 40402, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan.
¹⁶ Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
¹⁷ Department of Thoracic Surgery, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China. Electronic address: yongpeng@scu.edu.cn.
¹⁸ Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA. Electronic address: carlo.croce@osumc.edu.

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.

MeSH terms

Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology*
Down-Regulation
Drug Resistance, Neoplasm
Extracellular Signal-Regulated MAP Kinases / metabolism*
Gene Expression Regulation, Neoplastic
Humans
Karyopherins / chemistry
Karyopherins / metabolism*
Liver Neoplasms / genetics
Liver Neoplasms / metabolism
Liver Neoplasms / pathology*
MicroRNAs / genetics*
NIMA-Interacting Peptidylprolyl Isomerase / metabolism*
Phosphorylation
Prognosis
Protein Conformation

Substances

Karyopherins
MIRN122 microRNA, human
MicroRNAs
NIMA-Interacting Peptidylprolyl Isomerase
XPO5 protein, human
Extracellular Signal-Regulated MAP Kinases
PIN1 protein, human

Abstract

MeSH terms

Substances

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