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.

MicroRNA-30d-5p inhibits tumour cell proliferation and motility by directly targeting CCNE2 in non-small cell lung cancer

“…When considering downstream targets for the oncogenic functions of miR-30d, it is interesting to note that inhibiting KPNB1 expression induces MPNST cell apoptosis [17], and miR30d-5p inhibits proliferation and colony formation of anaplastic thyroid carcinoma cells by targeting EZH2 [21]. In NSCLC cells, we found that CCNE2 silencing significantly suppressed cell proliferation and induced G1/S cell cycle arrest (as expected).…”

“…miR-30d-5p can influence cell survival and apoptosis in malignant peripheral nerve sheath tumour cells (MPNSTs) and renal cell carcinoma, respectively [17,18]. miR-30d has been shown to be overexpressed in medulloblastoma and prostate cancer [19,20].…”

miR‐30d is related to asbestos exposure and inhibits migration and invasion in NCI‐H2452 cells

“…miR‐30d is involved in cell survival and apoptosis in malignant peripheral nerve sheath tumor cells and in renal cell carcinoma 33, 34. By means of a series of in vitro assays, we uncovered that the overexpression of miR‐30d could inhibit cell proliferation, migration, and invasion and promote apoptosis in pleural MM cells.…”

Epigenetic Regulators: New Therapeutic Targets for Soft Tissue Sarcoma

“…High EZH2 expression has also been found in Ewing sarcoma, in which EWS/FLI1 directly activates EZH2 expression and inhibits tumor cell differentiation [42] . Recently, the function of EZH2 and the molecular mechanisms that are regulated by EZH2 in MPNST pathogenesis have been investigated [43] . EZH2 expression is significantly higher in MPNST tumor samples than in neurofibromas and normal nerve tissues.…”

“…In multiple MPNST cell lines, EZH2 protein expression is also higher than that in Schwann cells which are the potential origin of MPNST. Genetic knockdown of EZH2 in NF1-related and non-NF1-related MPNST cell lines induces cell death in vitro and inhibits tumor growth in vivo [43] . Evidences demonstrate that upregulated EZH2 in MPNST cells inhibits miR-30d expression via binding to miR-30d promoter.…”