title: EZH2-miR-30d-KPNB1 pathway regulates malignant peripheral nerve sheath tumour cell survival and tumourigenesis.
abstract: Malignant peripheral nerve sheath tumours (MPNSTs), which develop sporadically or from neurofibromatosis, recur frequently with high metastatic potential and poor outcome. The polycomb group protein enhancer of zeste homologue 2 (EZH2) is an important regulator for various human malignancies. However, the function of EZH2 in MPNSTs is unknown. Here we report that the EZH2-miR-30d-KPNB1 signalling pathway is critical for MPNST tumour cell survival in vitro and tumourigenicity in vivo. Up-regulated EZH2 in MPNST inhibits miR-30d transcription via promoter binding activity, leading to enhanced expression of the nuclear transport receptor KPNB1 that is inhibited by miR-30d targeting of KPNB1 3' UTR region. Furthermore, inhibition of EZH2 or KPNB1, or miR-30d over-expression, induces MPNST cell apoptosis in vitro and suppresses tumourigenesis in vivo. More importantly, forced over-expression of KPNB1 rescues MPNST cell apoptosis induced by EZH2 knockdown. Immunohistochemical analyses show that EZH2 and KPNB1 over-expression is observed in human MPNST specimens and is negatively associated with miR-30d expression. Our findings identify a novel signalling pathway involved in MPNST tumourigenesis, and also suggest that EZH2-miR-30d-KPNB1 signalling represents multiple potential therapeutic targetable nodes for MPNST.
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Sarcoma Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Pingyu
authors.initials: P
authors.lastname: Zhang
authors.forename: Jeannine
authors.initials: J
authors.lastname: Garnett
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Ghadah Abbas
authors.initials: GA
authors.lastname: Al Sannaa
authors.forename: Davis R
authors.initials: DR
authors.lastname: Igram
authors.forename: Alexander
authors.initials: A
authors.lastname: Lazar
authors.forename: Xiuping
authors.initials: X
authors.lastname: Liu
authors.forename: Changgong
authors.initials: C
authors.lastname: Liu
authors.forename: Raphael E
authors.initials: RE
authors.lastname: Pollock
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009442:Neurilemmoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D046888:Tissue Array Analysis; D015854:Up-Regulation; D028961:beta Karyopherins / Q000235:genetics / Q000378:metabolism*
chemical_list: C424166:KPNB1 protein, human; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D028961:beta Karyopherins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: EZH2; KPNB1; MPNST; miR-30d; tumourigenesis