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.
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA; Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Hui-Lung
authors.initials: HL
authors.lastname: Sun
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Ri
authors.initials: R
authors.lastname: Cui
authors.affiliation: Department of Thoracic Surgery, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: JianKang
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pathology, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Kun-Yu
authors.initials: KY
authors.lastname: Teng
authors.affiliation: Department of Human Sciences, Human Nutrition Program, College of Education and Human Ecology, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Yung-Hsuan
authors.initials: YH
authors.lastname: Hsiao
authors.affiliation: Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Nakanishi
authors.affiliation: 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.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Guqin
authors.initials: G
authors.lastname: Shi
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA; Department of Anesthesiology, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Esmerina
authors.initials: E
authors.lastname: Tili
authors.affiliation: Department of Pathology, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Huban
authors.initials: H
authors.lastname: Kutay
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.affiliation: ARC-NET Research Centre, University and Hospital Trust of Verona, Verona 37126, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Vicentini
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Han-Li
authors.initials: HL
authors.lastname: Huang
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City 25245, Taiwan.
authors.forename: Shih-Wei
authors.initials: SW
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Taewan
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zanesi
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Tae Jin
authors.initials: TJ
authors.lastname: Lee
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
authors.affiliation: 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.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Pathology, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Ghoshal
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA. Electronic address: carlo.croce@osumc.edu.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D028884:Karyopherins / Q000737:chemistry / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D011487:Protein Conformation
chemical_list: D028884:Karyopherins; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C446511:XPO5 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; C000606846:PIN1 protein, human
keywords: ERK; Exportin-5; Pin1; drug resistance; global downregulation; liver cancer; miR-122; miRNA; microtubule; nuclear export