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

Aylin Del Moral-Morales,Ignacio Camacho-Arroyo,Karina Hernández-Ortega,Juan Carlos González-Orozco,Karla Mariana Peña-Gutiérrez,Ana María Hernández-Vega

doi:10.3389/fendo.2022.703733

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.

Highlights

Astrocytomas are primary tumors generated by the malignization of glial cells, glial progenitors, or transformed neural stem cells
We evaluated the participation of the methyltransferase Enhancer of Zeste Homolog 2 (EZH2) on E2 mediated pro-oncogenic effects in GBM cells
Using in silico transcriptomic data of GBM samples, we analyzed if estrogen receptors (ERs) activities, as transcriptional regulators, could be related to those EZH2, as an approach to explore whether E2 mediates EZH2 activation through a genomic mechanism via its ERs

Summary

Introduction

Astrocytomas are primary tumors generated by the malignization of glial cells, glial progenitors, or transformed neural stem cells. According to their histopathological characteristics, the WHO classifies gliomas into four grades, grade IV or glioblastoma (GBM), as the most aggressive and frequent [1]. GBMs are characterized by being highly invasive and fast-growing so that patients have a low life expectancy (12 to 16 months after diagnosis). Because GBMs are more frequent in males than in females, the role of sex hormones such as progesterone, 17b-estradiol (E2), and testosterone in the incidence and progression of GBM has gained greater attention [4,5,6]. E2 concentration is higher in GBM biopsies than in low-grade gliomas [7]

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