title: Inhibition of EZH2 suppresses self-renewal and induces radiation sensitivity in atypical rhabdoid teratoid tumor cells.
abstract: BACKGROUND
  Overexpression of the Polycomb repressive complex 2 (PRC2) subunit Enhancer of Zeste 2 (EZH2) occurs in several malignancies, including prostate cancer, breast cancer, medulloblastoma, and glioblastoma multiforme. Recent evidence suggests that EZH2 may also have a role in rhabdoid tumors. Atypical teratoid/rhabdoid tumor (ATRT) is a rare, high-grade embryonal brain tumor that occurs most commonly in young children and carries a very poor prognosis. ATRTs are characterized by absence of the chromatin remodeling protein SMARCB1. Given the role of EZH2 in regulating epigenetic changes, we investigated the role of EZH2 in ATRT.
  
  
  METHODS
  Microarray analysis was used to evaluate expression of EZH2 in ATRT tumor samples. We used shRNA and a chemical inhibitor of EZH2 to examine the impact of EZH2 inhibition on cell growth, proliferation, and tumor cell self-renewal.
  
  
  RESULTS
  Here, we show that targeted disruption of EZH2 by RNAi or pharmacologic inhibition strongly impairs ATRT cell growth, suppresses tumor cell self-renewal, induces apoptosis, and potently sensitizes these cells to radiation. Using functional analysis of transcription factor activity, we found the cyclin D1-E2F axis to be repressed after EZH2 depletion in ATRT cells.
  
  
  CONCLUSIONS
  Our observations provide evidence that EZH2 disruption alters cell cycle progression and may be an important new therapeutic target, particularly in combination with radiation, in ATRT.
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children’s Hospital Colorado, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Alimova
authors.forename: Diane K
authors.initials: DK
authors.lastname: Birks
authors.forename: Peter S
authors.initials: PS
authors.lastname: Harris
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Knipstein
authors.forename: Sujatha
authors.initials: S
authors.lastname: Venkataraman
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
mesh_terms: D000293:Adolescent; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D016922:Cellular Senescence; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002648:Child; D000071221:Enhancer of Zeste Homolog 2 Protein; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D020411:Oligonucleotide Array Sequence Analysis; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018335:Rhabdoid Tumor / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D018874:Spheroids, Cellular; D013724:Teratoma / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2