Analysis of EZH2: micro-RNA network in low and high grade astrocytic tumors

Abstract

Enhancer of Zeste homologue2 (EZH2) is an epigenetic regulator that functions as oncogene in astrocytic tumors, however, EZH2 regulation remains little studied. In this study, we measured EZH2 levels in low (Gr-II,DA) and high grade (Gr-IV,GBM) astrocytic tumors and found significant increased EZH2 transcript level with grade(median DA-8.5, GBM-28.9).However, a different trend was reflected in protein levels, with GBMs showing high EZH2 LI(median-26.5) compared to DA (median 0.3). This difference in correlation of EZH2 protein and RNA levels suggested post-transcriptional regulation of EZH2, likely mediated by miRNAs. We selected eleven miRNAs that strongly predicted to target EZH2 and measured their expression. Three miRNAs (miR-26a-5p,miR27a-3p and miR-498) showed significant correlation with EZH2 protein, suggesting them as regulators of EZH2, however miR-26a-5p levels decreased with grade. ChIP analyses revealed H3K27me3 modifications in miR-26a promoter suggesting feedback loop between EZH2 and miR26a. We further measured six downstream miRNA targets of EZH2 and found significant downregulation of four (miR-181a/b and 200b/c) in GBM. Interestingly, EZH2 associated miRNAs were predicted to target 25 genes in glioma-pathway, suggesting their role in tumor formation or progression. Collectively, our work suggests EZH2 and its miRNA interactors may serve as promising biomarkers for progression of astrocytic tumors and may offer novel therapeutic strategies.

EZH2 suppression in glioblastoma shifts microglia toward M1 phenotype in tumor microenvironment

“…The oncogene EZH2 is of considerable interest as a potential therapeutic target in GBMs. It has been confirmed that EZH2 is highly expressed in GBM samples and cell lines [ 7 , 12 ], and abundance of EZH2 is associated with high GBM grades and poor survival [ 6 , 7 ]. Numerous studies report that knockdown of EZH2 by siEZH2 or function suppression by DZNep induce GBM growth inhibition [ 13 – 15 ] and EZH2 is well recognized to take part in multiple tumor processes such as cell cycle [ 14 ], proliferation [ 16 ], apoptosis [ 16 ], invasion and mobility [ 16 ], GBM stem cell differentiation and maintenance [ 17 , 18 ], tumor angiogenesis [ 19 ], etc.…”

KDM2B overexpression correlates with poor prognosis and regulates glioma cell growth

“… 34 The prognostic and biological role of EZH2 has been fully investigated in gliomas. 35 – 40 In addition, deactivation of EZH2 might alleviate many vital signals relating to glioma self-renewal, which suggests that EZH2 can act as a novel therapeutic factor for GBM. 41 A previous study identified EZH2 as a prognostic biomarker of survival rates in glioma patients undergoing resection treatment.…”

EZH2 overexpression is associated with poor prognosis in patients with glioma

“…The biological role and prognostic significance of EZH2 were extensively investigated in gliomas [21–26]. Regarding the prognostic value, various studies presented controversial results, which may confuse clinicians for selecting EZH2 for prognostication.…”