title: Epigenetic silencing and activation of transcription: influence on the radiation sensitivity of glioma cell lines.
abstract: To uncover the role of EZH2 and its opponent ASHL2, a polycomb and trithorax group protein, respectively, on the radioresponsiveness of glioma cell lines.
  
  
  
  Expression of EZH2 and ASHL2 was inhibited by siRNA in glioma cell lines. The effect on histone methylation, gene expression, DNA damage repair signaling, cell cycle checkpoints, apoptosis and tumor control were evaluated.
  
  
  
  Inhibition of EZH2 (EZH2i) led to a transcriptional dysregulation with upregulation of 544 and downregulation of 445 genes. In comparison, ASH2L inhibition (ASH2Li) had an opposed effect with upregulation of 289 and downregulation of 970 genes. EZH2i and ASH2Li significantly reduced methylation of H3K27 and increased methylation of H3K9, respectively. EZH2i and ASH2Li significantly increased and decreased the number of residual γH2AX foci at 24 h after IR, respectively. The former significantly increased radiation-induced cell cycle arrest in G2/M and apoptotic cell death, while ASH2Li decreased both. In addition, a significant shift of the radioresponse curve by -1.22 + 0.23 Gy (p < 0.0001) in the plaque monolayer assay was found after EZH2i in A7 but not in M059K.
  
  
  
  Overall, epigenetic modulation is a promising approach to evaluate the role of chromatin structure for the radioresponsiveness of glioma cell lines.
authors.affiliation: a Department of Radiotherapy , University Hospital Essen , Essen , Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: Sak
authors.affiliation: a Department of Radiotherapy , University Hospital Essen , Essen , Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Kübler
authors.affiliation: a Department of Radiotherapy , University Hospital Essen , Essen , Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Bannik
authors.affiliation: a Department of Radiotherapy , University Hospital Essen , Essen , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Groneberg
authors.affiliation: b Department of Biomathematics and Bioinformatics , Institute of Genetics and Biometry, Leibniz-Institute for Farm Animal Biology , Dummerstorf , Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Strunz
authors.affiliation: c Department of Safety and Radiation Protection , Forschungszentrum Jülich GmbH , Jülich , Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kriehuber
authors.affiliation: a Department of Radiotherapy , University Hospital Essen , Essen , Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stuschke
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D004307:Dose-Response Relationship, Radiation; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics* / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000528:radiation effects; D020868:Gene Silencing / Q000528:radiation effects; D005910:Glioma / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics* / Q000528:radiation effects
chemical_list: C485622:ASH2L protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: DNA repair; Epigenetic; apoptosis; polycomb; radiation sensitivity; trithorax