ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5
Journal
Cancer Cell
Journal Volume
30
Journal Issue
5
Pages
723-736
Date Issued
2016
Author(s)
Sun H.-L.
Cui R.
Zhou J.
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.
Hung M.-C.
Ghoshal K.
Teng C.-M.
Peng Y.
Croce C.M.
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. ? 2016 Elsevier Inc.
Subjects
drug resistance; ERK; Exportin-5; global downregulation; liver cancer; microtubule; miR-122; miRNA; nuclear export; Pin1
SDGs
Other Subjects
CD133 antigen; epithelial cell adhesion molecule; exportin 5; I kappa B kinase alpha; I kappa B kinase beta; microRNA 122; mitogen activated protein kinase; mitogen activated protein kinase 1; mitogen activated protein kinase 3; paclitaxel; peptidyl prolyl cis trans isomerase NIMA interacting 1; karyopherin; microRNA; MIRN122 microRNA, human; mitogen activated protein kinase; NIMA interacting peptidylprolyl isomerase; PIN1 protein, human; XPO5 protein, human; 3' untranslated region; Article; binding site; cancer prognosis; cancer resistance; cell nucleus; cell proliferation; cell viability; chemosensitivity; conformational transition; controlled study; crystal structure; down regulation; enzyme activation; human; human tissue; in vitro study; liver cell carcinoma; microtubule; microtubule assembly; mouse; nonhuman; nuclear export signal; priority journal; protein conformation; protein phosphorylation; RNA binding; upregulation; chemistry; drug resistance; gene expression regulation; genetics; liver cell carcinoma; liver tumor; metabolism; pathology; phosphorylation; prognosis; Carcinoma, Hepatocellular; Down-Regulation; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; Humans; Karyopherins; Liver Neoplasms; MicroRNAs; NIMA-Interacting Peptidylprolyl Isomerase; Phosphorylation; Prognosis; Protein Conformation
Type
journal article