Abstract
BackgroundEnhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator in cancer cell survival, epithelial-mesenchymal transition, and tumorigenesis. Inhibition of EZH2 has become a promising therapeutic option for various human malignancies. Previously, we demonstrated that the EZH2/miR-30d/karyopherin (importin) beta 1 (KPNB1) signaling pathway is critical for malignant peripheral nerve sheath tumor (MPNST) cell survival in vitro and for tumorigenesis in vivo. Here, we sought to determine the antitumor effects of pharmacological inhibition of EZH2 on MPNST in vitro and in vivo.MethodsWe investigated the effects of an EZH2 inhibitor, 3-deazaneplanocin A (DZNep), on MPNST cell cycle, survival and apoptosis in vitro and on MPNST xenograft tumor growth in vivo.ResultsWe found that DZNep treatment impaired MPNST cell viability and proliferation by inducing apoptosis and cell cycle arrest in vitro. Consistently, DZNep treatment also reduced EZH2 and KPNB1 protein levels and upregulated miR-30d expression in MPNST cells. Intraperitoneal administration of DZNep significantly suppressed MPNST tumor initiation and growth rates in a MPNST xenograft mouse model. Immunoblot and immunohistochemical analyses showed that DZNep downregulated EZH2/KPNB1 signaling in vivo, thereby inhibiting MPNST tumor cell proliferation, and induced cell death. We also found that EZH2 inhibited expression of another miR-30 family member, miR-30a, in MPNST cells. Similar to miR-30d, miR-30a inhibited KPNB1 by targeting the KPNB1 3’ untranslated region in MPNST cells. Our data also showed that EZH2 suppressed miR-200b expression and induced epithelial-mesenchymal transition in MPNST cells.ConclusionThese findings demonstrated that DZNep, an inhibitor of S-adenosyl-methionine–dependent methyltransferase, suppressed EZH2/miR-30a,d/KPNB1 signaling and blocked MPNST tumor cell growth and survival in vitro and in vivo. More importantly, our study indicated that pharmacological interference of EZH2 is a potential therapeutic approach for MPNST.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0325-1) contains supplementary material, which is available to authorized users.
Highlights
Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator in cancer cell survival, epithelialmesenchymal transition, and tumorigenesis
We hypothesized that EZH2 inhibitor deazaneplanocin A (DZNep) treatment would suppress malignant peripheral nerve sheath tumor (MPNST) cell proliferation and induce cell death of MPNST cells in vitro
We assessed whether MPNST724 and S462 cell cycle profiles were changed by DZNep treatment
Summary
Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator in cancer cell survival, epithelialmesenchymal transition, and tumorigenesis. Inhibition of EZH2 has become a promising therapeutic option for various human malignancies. We demonstrated that the EZH2/miR-30d/karyopherin (importin) beta 1 (KPNB1) signaling pathway is critical for malignant peripheral nerve sheath tumor (MPNST) cell survival in vitro and for tumorigenesis in vivo. Abnormal EZH2 expression has been associated with various human malignancies, including lymphoma and lung, breast, and prostate cancers [3]. EZH2 knockdown by RNA interference in MPNST cell lines induces MPNST cell apoptosis in vitro and inhibits MPNST tumor growth in vivo, suggesting that EZH2 is a potential therapeutic target in MPNST [5]
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