title: Targeting the enhancer of zeste homologue 2 in medulloblastoma.
abstract: Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 that catalyzes the trimethylation of histone H3 on Lys 27, and represses gene transcription. EZH2 enhances cancer-cell proliferation and regulates stem cell maintenance and differentiation. Here, we demonstrate that EZH2 is highly expressed in medulloblastoma, a highly malignant brain tumor of childhood, and this altered expression is correlated with genomic gain of chromosome 7 in a subset of medulloblastoma. Inhibition of EZH2 by RNAi suppresses medulloblastoma tumor cell growth. We show that 3-deazaneplanocin A, a chemical inhibitor of EZH2, can suppress medulloblastoma cell growth partially by inducing apoptosis. Suppression of EZH2 expression diminishes the ability of tumor cells to form spheres in culture and strongly represses the ability of known oncogenes to transform neural stem cells. These findings establish a role of EZH2 in medulloblastoma and identify EZH2 as a potential therapeutic target especially in high-risk tumors.
authors.affiliation: Department of Pediatrics, The Children's Hospital and University of Colorado, Anschutz Medical Campus, CO, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Alimova
authors.forename: Sujatha
authors.initials: S
authors.lastname: Venkataraman
authors.forename: Peter
authors.initials: P
authors.lastname: Harris
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Adrian
authors.initials: A
authors.lastname: Dubuc
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000293:Adolescent; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016022:Case-Control Studies; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002531:Cerebellum / Q000378:metabolism; D002648:Child; D003114:Colony-Forming Units Assay; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005434:Flow Cytometry; D006657:Histones / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D063151:Polycomb Repressive Complex 2; D034741:RNA, Small Interfering / Q000235:genetics*; D018874:Spheroids, Cellular; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D034741:RNA, Small Interfering; D014157:Transcription Factors; C048460:3-deazaneplanocin; D008156:Luciferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D000241:Adenosine