title: Histone deacetylase inhibitors sensitize human non-small cell lung cancer cells to ionizing radiation through acetyl p53-mediated c-myc down-regulation.
abstract: BACKGROUND
  Histone deacetylase inhibitors (HDACIs) induce growth arrest and apoptosis in cancer cells. In addition to their intrinsic anticancer properties, HDACIs modulate cellular responses to ionizing radiation (IR). We examined the molecular mechanism(s) associated with the radiosensitizing effects of HDACIs in human lung cancer cells.
  
  
  METHODS
  Lung cancer cells were pretreated with the appropriate concentrations of suberoylanilide hydroxamic acid or trichostatin A. After 2 hours, cells were irradiated with various doses of γ-IR, and then we performed 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, fluorescence-activated cell sorting analysis, clonogenic assay, and Western blotting to detect cell viability or apoptosis and changes of specific proteins expression levels.
  
  
  RESULTS
  In this study, we showed that HDACIs (including suberoylanilide hydroxamic acid and trichostatin A) and IR synergistically trigger cell death in human non-small cell lung cancer cells. Cell viability and clonogenic survival were markedly decreased in cultures cotreated with HDACIs and IR. Interestingly, p53 acetylation at lysine 382 was significantly increased, and c-myc expression simultaneously down-regulated in cotreated cells. Radiosensitization by HDACIs was inhibited on transfection with small interfering RNA against p53 and c-myc overexpression, supporting the involvement of p53 and c-myc in this process. Furthermore, c-myc down-regulation and apoptotic cell death coinduced by IR and HDACI were suppressed in cells transfected with mutant K382R p53 and C135Y p53 displaying loss of acetylation at lysine 382 and DNA-binding activity, respectively.
  
  
  CONCLUSIONS
  Our results collectively demonstrate that the degree of radiosensitization by HDACIs is influenced by acetyl p53-mediated c-myc down-regulation.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gu, South Korea.
authors.forename: Sung-Keum
authors.initials: SK
authors.lastname: Seo
authors.forename: Hyeon-Ok
authors.initials: HO
authors.lastname: Jin
authors.forename: Sang-Hyeok
authors.initials: SH
authors.lastname: Woo
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Sungkwan
authors.initials: S
authors.lastname: An
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Seok-Il
authors.initials: SI
authors.lastname: Hong
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Lee
authors.forename: Tae-Boo
authors.initials: TB
authors.lastname: Choe
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
mesh_terms: D000107:Acetylation / Q000187:drug effects / Q000528:radiation effects; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D015536:Down-Regulation; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011838:Radiation-Sensitizing Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; D000077337:Vorinostat