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EZH2–miR ‐30d– KPNB1 pathway regulates malignant peripheral nerve sheath tumour cell survival and tumourigenesis
Author(s) -
Zhang Pingyu,
Garnett Jeannine,
Creighton Chad J,
Al Sannaa Ghadah Abbas,
Igram Davis R,
Lazar Alexander,
Liu Xiuping,
Liu Changgong,
Pollock Raphael E
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4294
Subject(s) - ezh2 , cancer research , gene knockdown , biology , apoptosis , gene expression , genetics , gene
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 . Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.