title: PCI-24781 down-regulates EZH2 expression and then promotes glioma apoptosis by suppressing the PIK3K/Akt/mTOR pathway.
abstract: PCI-24781 is a novel histone deacetylase inhibitor that inhibits tumor proliferation and promotes cell apoptosis. However, it is unclear whether PCI-24781 inhibits Enhancer of Zeste 2 (EZH2) expression in malignant gliomas. In this work, three glioma cell lines were incubated with various concentrations of PCI-24781 (0, 0.25, 0.5, 1, 2.5 and 5 μM) and analyzed for cell proliferation by the MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay and colony formation, and cell cycle and apoptosis were assessed by flow cytometry. The expression of EZH2 and apoptosis-related proteins was assessed by western blotting. Malignant glioma cells were also transfected with EZH2 siRNA to examine how PCI-24781 suppresses tumor cells. EZH2 was highly expressed in the three glioma cell lines. Incubation with PCI-24781 reduced cell proliferation and increased cell apoptosis by down-regulating EZH2 in a concentration-dependent manner. These effects were simulated by EZH2 siRNA. In addition, PCI-24781 or EZH2 siRNA accelerated cell apoptosis by down-regulating the expression of AKT, mTOR, p70 ribosomal protein S6 kinase (p70s6k), glycogen synthase kinase 3A and B (GSK3a/b) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1). These data suggest that PCI-24781 may be a promising therapeutic agent for treating gliomas by down-regulating EZH2 which promotes cell apoptosis by suppressing the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of the rapamycin (mTOR) pathway.
authors.affiliation: Department of Neurosurgery , Xinqiao Hospital , Third Military Medical University , Chongqing , China .
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery , Xinqiao Hospital , Third Military Medical University , Chongqing , China .
authors.forename: Shengqing
authors.initials: S
authors.lastname: Lv
authors.affiliation: Department of Neurosurgery , Xinqiao Hospital , Third Military Medical University , Chongqing , China .
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery , Xinqiao Hospital , Third Military Medical University , Chongqing , China .
authors.forename: Zhenle
authors.initials: Z
authors.lastname: Zang
authors.affiliation: Department of Neurosurgery , Xinqiao Hospital , Third Military Medical University , Chongqing , China .
authors.forename: Junyi
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Neurosurgery , Xinqiao Hospital , Third Military Medical University , Chongqing , China .
authors.forename: Ning
authors.initials: N
authors.lastname: An
authors.affiliation: Department of Neurosurgery , Xinqiao Hospital , Third Military Medical University , Chongqing , China .
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery , Guiyang 300 Hospital , Zunyi Medical College , Guizhou , China .
authors.forename: Yechun
authors.initials: Y
authors.lastname: Song
keywords: EZH2; PCI-24781; PIK3K/Akt/mTOR signaling pathway; malignant gliomas