miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis

Abstract

Background Glioblastoma (GBM) is a malignant brain tumor with dismal prognosis. GBM patients have a median survival of less than 2 years. GBM is characterized by fast cell proliferation, infiltrative migration, and by the induction of angiogenesis. MicroRNAs and polycomb group (PcG) proteins have emerged as important regulators of gene expression. Methods Here we determined that miR-101 is down-regulated in GBM, resulting in overexpression of the miR-101 target PcG protein EZH2, a histone methyltransferase affecting gene expression profiles in an epigenetic manner. Results Inhibition of EZH2 in vitro by pre-miR-101, EZH2 siRNA, or small molecule DZNep, attenuated GBM cell growth, migration/invasion, and GBM-induced endothelial tubule formation. In addition, for each biological process we identified ontology-associated transcripts that significantly correlate with EZH2 expression. Inhibition of EZH2 in vivo by systemic DZNep administration in a U87-Fluc-mCherry GBM xenograft mouse imaging model resulted in reduced tumor growth. Conclusion Our results indicate that EZH2 has a versatile function in GBM progression and that its overexpression is at least partly due to decreased miR-101 expression. Inhibition of EZH2 may be a potential therapeutic strategy to target GBM proliferation, migration, and angiogenesis.

Cancer Angiogenesis Induced by Kaposi Sarcoma–Associated Herpesvirus Is Mediated by EZH2

“…EZH2 has been shown to regulate cancer angiogenesis (22, 24). We determined whether KSHV-induced up-regulation of EZH2 contributed to KSHV-induced angiogenesis.…”

“…Moreover, mutation of EZH2 Y641, which results in gain-of-function, has been described in lymphomas (21). Recent studies have shown that both VEGF and FGF2 induce angiogenesis through up-regulation of EZH2 expression, and inhibition of EZH2 attenuated the cell proliferation, migration and tubule formation of Glioblastoma cells (18, 22–24). …”

Upregulation of miR-107 Inhibits Glioma Angiogenesis and VEGF Expression

“…These investigations focused mainly on two aspects: impact of microRNA expression on glioma-associated ECs, such as miR-125b (Smits et al 2012), miR-296 (Wurdinger et al 2008), and miR-101 (Smits et al 2010), and microRNA expression in glioma cells and function in angiogenesis. For instance, miRNA-26a has been shown to act as an oncogene and promote glioma angiogenesis, while miR-128 suppresses gliomal growth and angiogenesis through targeting p70S6K1 (Qian et al 2013;Shi et al 2012).…”

Deregulation of Histone-Modifying Enzymes and Chromatin Structure Modifiers Contributes to Glioma Development

“…Quantitative PCR and immunohistochemistry demonstrated that EZH2 is more expressed in GBMs than in low-grade gliomas [33]. EZH2 expression was detected in tumor cells by immunohistochemistry in GBM samples; no detectable expression was observed in adjacent brain parenchyma [33,35,54]. The TCGA data analysis revealed that other PcG genes are commonly overexpressed in GBMs.…”

“…Immunocytochemical studies showed that the number of tumor cells with nuclear localization of EZH2 is greater around tumor vessels and at the invasive front in human glioma specimens [53]. Silencing of EZH2 expression led to cell cycle arrest, decrease in cell proliferation, invasion and angiogenesis, and induced apoptosis in vitro [37,[54][55][56][57] and in vivo [53,54]. Pharmacological inhibition of EZH2 function with 3-deazaneplanocin A (DZNep) induced transcriptome changes consistent with the EZH2 role as a repressor of gene expression.…”