title: Isotype-Specific Inhibition of Histone Deacetylases: Identification of Optimal Targets for Radiosensitization.
abstract: OBJECTIVE
  Histone deacetylase (HDAC) inhibitors radiosensitize tumor cells. To elucidate mechanisms underlying radiosensitization by HDAC inhibition, understanding of differential contributions of HDAC isotypes is needed. The aim of this study was to investigate involvement of known HDAC isotypes in modulation of cellular radiosensitivity.
  
  
  METHODS
  Because pharmacologic HDAC inhibitors lack isotype-specificity, RNA interference against 11 HDAC isotypes was used to inhibit HDAC in an isotype-specific manner. Radiation cell survival was evaluated using a clonogenic assay in SQ20B cells transfected with small interfering RNA specifically targeting HDAC isotypes. Immunocytochemistry was performed for detection of γH2AX foci. Protein expression was measured using Western blotting.
  
  
  RESULTS
  Among 11 HDAC isotypes tested, specific inhibition of 7 isotypes (HDAC1, HDAC3, HDAC4, HDAC6, HDAC7, HDAC10, and HDAC11) enhanced radiation lethality in SQ20B cells. Radiosensitization by inhibition of these HDAC isotypes was accompanied by delay of DNA double strand break repair. Radiosensitivity of SQ20B cells was not altered by selective inhibition of the remaining four isotypes (HDAC2, HDAC5, HDAC8, and HDAC9). Inhibition of HDAC isotypes resulted in downregulation of various proteins involved in pro-survival and DNA damage repair pathways.
  
  
  CONCLUSIONS
  Isotype-specificity exists in HDAC inhibition-induced radiosensitization. Different HDAC isotypes are differentially involved in modulation of cellular radiosensitivity.
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.|Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Korea.
authors.forename: Jin Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Moon
authors.affiliation: Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Mina
authors.initials: M
authors.lastname: No
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.|Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Jae Jin
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Choi
authors.affiliation: Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Bong Jun
authors.initials: BJ
authors.lastname: Cho
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.|Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Jae Sung
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.|Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Il Han
authors.initials: IH
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.|Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: In Ah
authors.initials: IA
authors.lastname: Kim
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D015536:Down-Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
chemical_list: D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D006655:Histone Deacetylases
keywords: Histone deacetylases; Ionizing radiation; RNA interference; Radiation