Email this article Research Papers:
miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis
Abstract
Received: December 1, 2010, Accepted: January 3, 2010, Published: January 3, 2010
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.
Author Information
Michiel Smits
Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
Jonas Nilsson
Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
Shahryar E. Mir
Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
Petra M. van der Stoop
Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
Esther Hulleman
Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
Johanna M. Niers
Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA, USA
Phillip C. de Witt Hamer
Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
Victor E. Marquez
Laboratory of Medicinal Chemistry, Center for Cancer Research, NCI-Frederick, MD, USA
Jacqueline Cloos
Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
Anna M. Krichevsky
Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
David P. Noske
Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
Bakhos A. Tannous
Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA, USA
Thomas Würdinger
Primary Contact
_
Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA, USA
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 205
Copyright © Impact Journals LLC 2008