Histone deacetylase inhibitors enhance phosphorylation of histone H2AX after ionizing radiation.
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.
Zhang
Yubin
Y
Division of Molecular Oncology and Molecular Diagnosis, Graduate School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
Adachi
Masaaki
M
Zou
Huichao
H
Hareyama
Masato
M
Imai
Kohzoh
K
Shinomura
Yasuhisa
Y
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
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