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.

Role of several histone lysine methyltransferases in tumor development

“…In glioma stem cells, EZH2 is a known target of the MELK-FOXM1 complex, having a critical role in promoting resistance to radiation ( 58 ). In glioma and clear cell renal cell carcinoma, downregulation of EZH2 expression can reduce cell proliferation and increase cell apoptosis ( 59 , 60 ). Furthermore, in non small-cell lung cancer, EZH2 silencing alters the cell cycle by inducing G 2 /M arrest ( 61 ).…”

Schisandrin B suppresses glioma cell metastasis mediated by inhibition of mTOR/MMP-9 signal pathway

“…PI3K/Akt/mTOR signaling, one of the three major signaling pathway that have been identified as important in cancer, is highly active in glioma and plays a pivotal role in cell survival, proliferation, and angiogenesis, and is frequently deregulated in human cancer [14]. Notably, various antitumor substances, such as PCI-24781 and progesterone, have been proved to against glioma via inactivating PI3K/Akt/mTOR signal [3,23]. Background: Malignant glioma is the aggressive tumor in the brain and is characterized by high morbidity, high mortality.…”

Deregulacja mechanizmów epigenetycznych w nowotworach Marta Maleszewska*,

“…Increasing evidence supports involvement of histone methyltransferase EZH2 (Enhancer of zeste homolog 2) in regulation of cell proliferation, apoptosis, invasion and angiogenesis in vitro [22][23][24][25][26] and in vivo [26,27]. EZH2 is the catalytic subunit of Polycomb repressive complex 2 (PRC2), which targets lysine 27 of histone H3.…”