title: Histone deacetylase inhibitors enhance phosphorylation of histone H2AX after ionizing radiation.
abstract: OBJECTIVE
  Histone deacetylase (HDAC) inhibitors are believed to be promising radiosensitizers. To explore their effects on ionizing radiation (IR), we examined whether the HDAC inhibitors m-carboxycinnamic acid bis-hydroxamide (CBHA) and depsipeptide FK228 affect H2AX phosphorylation (gamma-H2AX), a landmark of DNA double-strand breaks after IR exposure.
  
  
  METHODS
  We evaluated the effects of the HDAC inhibitors on clonogenic assay in human lung carcinoma A549 cells and progression of A549 xenograft tumors. IR-induced DNA damage was evaluated by histone gamma-H2AX. Histone hyperacetylation was induced by overexpression of histone acetyltransferase p300 and evaluated by Western blots.
  
  
  RESULTS
  M-carboxycinnamic acid bishydroxyamide pretreatment radiosensitized A549 cells and strongly inhibited A549 xenograft tumor progression. CBHA and FK228, but not 5-fluorouracil, enhanced IR-induced gamma-H2AX in A549 and other cancer cell lines. Overexpression of p300 similarly augmented IR-induced gamma-H2AX.
  
  
  CONCLUSIONS
  The results of this study suggest that HDAC inhibitors enhance IR-induced gamma-H2AX, most likely through histone hyperacetylation, and radiosensitize various cancers.
authors.affiliation: Division of Molecular Oncology and Molecular Diagnosis, Graduate School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Masaaki
authors.initials: M
authors.lastname: Adachi
authors.forename: Huichao
authors.initials: H
authors.lastname: Zou
authors.forename: Masato
authors.initials: M
authors.lastname: Hareyama
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology*; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D047630:Depsipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009281:Naphthalenes / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011753:Pyrones / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
chemical_list: D018797:Cell Cycle Proteins; D002934:Cinnamates; D004247:DNA; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D005472:Fluorouracil; D051548:Histone Acetyltransferases; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009281:Naphthalenes; D011753:Pyrones; D011838:Radiation-Sensitizing Agents; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C468783:H2AX protein, human; C111238:carboxycinnamic acid bishydroxamide; C444426:splitomicin; C087123:romidepsin