Inhibition of EZH2 suppresses self-renewal and induces radiation sensitivity in atypical rhabdoid teratoid tumor cells

Abstract

Our observations provide evidence that EZH2 disruption alters cell cycle progression and may be an important new therapeutic target, particularly in combination with radiation, in ATRT.

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…63 In addition, the SNF5 protein has a role in histone acetylation. 64,65 Inhibition of histone deacetylases (HDACs) has been found to specifically restore normal expression of proteins involved in cell cycle, originally altered in ATRT cells, through promoter histone H3 and H4 acetylation, recapitulating the effect of SNF5 restoration in ATRT cells. 65 …”

“…Targeted disruption of EZH2 also strongly impairs ATRT cell growth, suppresses tumor cell self-renewal, induces apoptosis, and potently sensitizes these cells to radiation. 64 Inhibitors of the catalytic activity of EZH2 have been developed, and suppressing global H3K27 methylation converges upon a common structural feature, a pyridone group, which is required for high affinity target binding (reviewed in 71 ). These inhibitors achieve dose-dependent induction of gene expression, confirming the role of the PRC2 complex in gene silencing, although a prolonged inhibition of EZH2 catalytic activity is required to reduce H3K27me3 to levels that are sufficient to alter patterns of gene expression.…”

“…Indeed, DZNep potently suppresses ATRT cell growth, leads to cell cycle alterations, increases apoptosis, potentiates the effect of radiation, decreases key cellular signal transduction pathways, and inhibits tumor sphere formation. 64 The first generation EZH2 inhibitors have recently entered phases I and II clinical trials. Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of EZH2 currently being tested in clinical trials for patients having malignant tumors, including ATRT (NCT02875548, NCT02601950, including in pediatric patients NCT02601937) ( Table 2).…”

Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth

“…INI1-deficient BT12 and BT16 ATRT cell lines 11 were propagated as monolayers in complete medium consisting of Dulbecco ′ s modified Eagle medium (DMEM, GIBCO #11965) supplemented with 10% fetal bovine serum (FBS) and nonessential amino acids. INI1-deficient CHLA02-ATRT cells 12 were obtained from the American Type Culture Collection and maintained as a neurosphere culture in medium consisting of Neurobasal-A medium (GIBCO #10888, Invitrogen) supplemented with N-2 (Invitrogen), B27 (Invitrogen), EGF (20 ng/mL, Sigma), and FGF (20 ng/mL, Peprotech).…”

EZH2 Inhibitor GSK126: Metabolism, drug transporter and rat pharmacokinetic studies

“…Next day, the cell suspension was centrifuged at maximum speed and the supernatant containing the histones was examined for the expression of histones by western blotting. The standard procedure was performed with a rabbit antiH3K27Me3 and anti-H3 antibodies (Active Motif) (Alimova et al, 2013).…”