title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Smits
authors.forename: Jonas
authors.initials: J
authors.lastname: Nilsson
authors.forename: Shahryar E
authors.initials: SE
authors.lastname: Mir
authors.forename: Petra M
authors.initials: PM
authors.lastname: van der Stoop
authors.forename: Esther
authors.initials: E
authors.lastname: Hulleman
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Niers
authors.forename: Phillip C
authors.initials: PC
authors.lastname: de Witt Hamer
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
authors.forename: Anna M
authors.initials: AM
authors.lastname: Krichevsky
authors.forename: David P
authors.initials: DP
authors.lastname: Noske
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
authors.forename: Thomas
authors.initials: T
authors.lastname: Würdinger
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D063151:Polycomb Repressive Complex 2; D034741:RNA, Small Interfering / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2