title: EZH2 is essential for glioblastoma cancer stem cell maintenance.
abstract: Overexpression of the polycomb group protein enhancer of zeste homologue 2 (EZH2) occurs in diverse malignancies, including prostate cancer, breast cancer, and glioblastoma multiforme (GBM). Based on its ability to modulate transcription of key genes implicated in cell cycle control, DNA repair, and cell differentiation, EZH2 is believed to play a crucial role in tissue-specific stem cell maintenance and tumor development. Here, we show that targeted pharmacologic disruption of EZH2 by the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep), or its specific downregulation by short hairpin RNA (shRNA), strongly impairs GBM cancer stem cell (CSC) self-renewal in vitro and tumor-initiating capacity in vivo. Using genome-wide expression analysis of DZNep-treated GBM CSCs, we found the expression of c-myc, recently reported to be essential for GBM CSCs, to be strongly repressed upon EZH2 depletion. Specific shRNA-mediated downregulation of EZH2 in combination with chromatin immunoprecipitation experiments revealed that c-myc is a direct target of EZH2 in GBM CSCs. Taken together, our observations provide evidence that direct transcriptional regulation of c-myc by EZH2 may constitute a novel mechanism underlying GBM CSC maintenance and suggest that EZH2 may be a valuable new therapeutic target for GBM management.
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Mario-Luca
authors.initials: ML
authors.lastname: Suvà
authors.forename: Nicolò
authors.initials: N
authors.lastname: Riggi
authors.forename: Michalina
authors.initials: M
authors.lastname: Janiszewska
authors.forename: Ivan
authors.initials: I
authors.lastname: Radovanovic
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Stehle
authors.forename: Karine
authors.initials: K
authors.lastname: Baumer
authors.forename: Marie-Aude
authors.initials: MA
authors.lastname: Le Bitoux
authors.forename: Denis
authors.initials: D
authors.lastname: Marino
authors.forename: Luisa
authors.initials: L
authors.lastname: Cironi
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Virginie
authors.initials: V
authors.lastname: Clément
authors.forename: Ivan
authors.initials: I
authors.lastname: Stamenkovic
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation; D000071221:Enhancer of Zeste Homolog 2 Protein; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D063151:Polycomb Repressive Complex 2; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2