Abstract
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. 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. 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. 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.
Highlights
GBM remains among the most devastating cancers with a median survival of less than 15 months and virtually no survival beyond five years [1]
We show that miR-101 is down-regulated in GBM cells, resulting in increased EZH2 expression and enhanced GBM cell proliferation, migration, and angiogenesis
Increased EZH2 expression correlated with glioma grade and glioma recurrence (Fig. 1B), suggesting that EZH2 could be a marker for glioma aggressiveness
Summary
GBM remains among the most devastating cancers with a median survival of less than 15 months and virtually no survival beyond five years [1]. Evidence supporting the critical role of proliferation, migration and angiogenesis in the biological behavior of these tumors has led to a variety of studies on the basic mechanisms involved. GBM cells are highly proliferative but are notorious because of their capacity to migrate through the brain parenchyma and their ability to induce angiogenic blood vessel sprouting. Several factors are involved in the angiogenesis process, which results in recruitment, proliferation and alignment of endothelial blood vessel cells through a complex interaction between endothelial cells and tumor cells [2]. MiRNAs comprise a large group of endogenous non-coding RNAs that can block mRNA translation or negatively regulate mRNA stability and thereby play a central role in the regulation of gene expression [3]. MicroRNAs and polycomb group (PcG) proteins have emerged as important regulators of gene expression
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