EZH2–miR‐30d–KPNB1 pathway regulates malignant peripheral nerve sheath tumour cell survival and tumourigenesis. Issue 3 (February 2014)

• Record Type: Journal Article
• Authors: Zhang, Pingyu; Garnett, Jeannine; Creighton, Chad J; Al Sannaa, Ghadah Abbas; Igram, Davis R; Lazar, Alexander; Liu, Xiuping; Liu, Changgong; Pollock, Raphael E
• Is Part Of: Journal of pathology. Volume 232:Issue 3(2014)
• Page Start: 308
• Page End: 318
• Publication Date: 2014-02
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4294
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main" id="path4294-abs-0001"> <title>Abstract</title> <p id="path4294-para-0001"> <bold>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 <italic>in vitro</italic> and tumourigenicity <italic>in vivo</italic>. 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 <italic>KPNB1</italic> 3′ UTR region. Furthermore, inhibition of EZH2 or KPNB1, or miR‐30d over‐expression, induces MPNST cell apoptosis <italic>in vitro</italic> and suppresses tumourigenesis <italic>in vivo</italic>. 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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</bold> </p> </abstract>