EZH2 Mediates Proliferation, Migration, and Invasion Promoted by Estradiol in Human Glioblastoma Cells

Abstract

Glioblastomas (GBM) are the most frequent and aggressive brain tumors. 17β-estradiol (E2) increases proliferation, migration, and invasion of human GBM cells; however underlying mechanisms are no fully understood. Zeste 2 Enhancer Homologous enzyme (EZH2) is a methyltransferase part of Polycomb 2 repressor complex (PRC2). In GBM, EZH2 is overexpressed and involved in the cell cycle, migration, and invasion processes. We studied the role of EZH2 in the pro-oncogenic actions of E2 in human GBM cells. EZH2 gene silencing and pharmacological inhibition of EZH2 blocked proliferation, migration, and invasion of GBM cells induced by E2. We identified in silico additional putative estrogen response elements (EREs) at the EZH2 promoter, but E2 did not modify EZH2 expression. In silico analysis also revealed that among human GBM samples, EZH2 expression was homogeneous; in contrast, the heterogeneous expression of estrogen receptors (ERs) allowed the classification of the samples into groups. Even in the GBM cluster with high expression of ERs and those of their target genes, the expression of PCR2 target genes did not change. Overall, our data suggest that in GBM cells, pro-oncogenic actions of E2 are mediated by EZH2, without changes in EZH2 expression and by mechanisms that appear to be unrelated to the transcriptional activity of ERs.

Bioenergetic Profiling in Glioblastoma Multiforme Patients with Different Clinical Outcomes

“…EZH2 is a S-adenosyl-L-methionine (SAM)-dependent methyltransferase, and its role as an epigenetic modulator in different types of cancer has been widely investigated. In GBM, EZH2 overexpression has been correlated with poor prognosis [ 57 , 58 ]. Although little is known about the mechanistic aspects of EZH2 activity in GBM, the inhibition of EZH2 expression by miR-340 in triple negative breast cancer has led to decreased levels of miR-21, revealing a key miRNA network pathway [ 59 ].…”

First-in-Class Dual EZH2-HSP90 Inhibitor Eliciting Striking Antiglioblastoma Activity In Vitro and In Vivo

“…Methyl 3′-(2,4-Bis(benzyloxy)-5-isopropyl-N-methylbenzamido)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-[1,1′-biphenyl]-3-carboxylate (30). Intermediate 30 was synthesized in 70% yield from starting material 21 like that described for the synthesis of compound 26.…”

“…An extensive literature survey led us to arrive at the emerging candidature of EZH2 as an epigenetic target for GBM. EZH2, a crux subunit of the Polycomb Repressive Complex (PRC2), is responsible for methylating lysine 27 (mono-, di-, and trimethylation) in histone H3 (H3K27) and H3K27me3 is more frequently interlinked with transcriptional repression. − Notably, EZH2 is overexpressed in cancer stem cells of malignant tumors and plays a critical role in cancer stem cell expansion and maintenance. − Several key revelations ascertain the involvement of EZH2 in GBM initiation and progression, such as (i) involvement of miR-206/Twist axis in EZH2-regulated malignancy of GBM cells, (ii) pro-oncogenic actions of Estradiol (proliferation, migration, and invasion) by EZH2 in GBM cells, and (iii) direct transcriptional regulation of c-myc by EZH2 leading to the maintenance of GSCs . To validate EZH2 as a therapeutic target in GBM and capitalize on the aforementioned revelations, several EZH2 inhibitors (Figure ) were evaluated (monotherapy/combination therapy) − and optimistic results were attained, for instance, (i) GSK343, a highly potent and selective EZH2 inhibitor, demonstrated the ability to counteract GBM progression via modulation of canonical/noncanonical NF -κB/IκBα pathways and immune response; (ii) a cocktail of tazemetostat (EZH2 inhibitor) and PI-103 (PI3K inhibitor) exerted significant reduction in GBM progression (U-87 cells); (iii) HOTAIR-EZH2 inhibitor AC1Q3QWB in combination with GSK-LSD1 inhibitor elicited enhanced antitumor efficacy in GBM patient-derived xenograft (PDX) models; (iv) combination of HOTAIR-EZH2 inhibitor (AQB) and palbociclib inhibitors suppressed the cell cycle in gliomas with high expression of EZH2 and low expression of CWF19L1; and (v) treatment with EZH2 inhibitors MC4040 and MC4041 led to impairment of primary GBM cell viability and weakened the aggressive malignant phenotype by reducing angiogenesis …”

PRMT6 facilitates EZH2 protein stability by inhibiting TRAF6-mediated ubiquitination degradation to promote glioblastoma cell invasion and migration

“…To elucidate how PRMT6 enhances the invasion of GBM cells, we rst analyzed the previously completed proteomic data [19] and found that the protein level of EZH2 was signi cantly down-regulated in PRMT6de cient U87 cells. EZH2 has been con rmed to be a key regulator of enhanced glioma cell invasiveness [24]. Therefore, to explore whether PRMT6 has a regulatory effect on EZH2 in GBM cells, we examined the in uence of PRMT6 silencing or overexpression on EZH2 expression.…”

“…EZH2 serves as a crucial intermediary regulatory factor that enhances proliferation, migration, and invasion of glioma cells [24]. Studies have demonstrated that reducing EZH2 levels can decrease the invasive, migratory, and proliferative abilities of glioma cells, while also promoting apoptotic processes [25].…”