Histone Deacetylase Inhibitors Enhance Phosphorylation of Histone H2AX After Ionizing Radiation

Int J Radiat Oncol Biol Phys. 2006 Jul 1;65(3):859-66. doi: 10.1016/j.ijrobp.2006.03.019.

Abstract

Purpose: 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 and materials: 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.

Conclusion: The results of this study suggest that HDAC inhibitors enhance IR-induced gamma-H2AX, most likely through histone hyperacetylation, and radiosensitize various cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cinnamates / pharmacology*
  • DNA / radiation effects
  • DNA Damage
  • Depsipeptides / pharmacology*
  • Enzyme Inhibitors / pharmacology*
  • Fluorouracil / pharmacology
  • Histone Acetyltransferases / metabolism*
  • Histone Deacetylase Inhibitors*
  • Histones / metabolism*
  • Humans
  • Mice
  • Mice, Nude
  • Naphthalenes / pharmacology
  • Phosphorylation / drug effects
  • Pyrones / pharmacology
  • Radiation-Sensitizing Agents / pharmacology*
  • Transcription Factors / metabolism*
  • p300-CBP Transcription Factors

Substances

  • Cell Cycle Proteins
  • Cinnamates
  • Depsipeptides
  • Enzyme Inhibitors
  • H2AX protein, human
  • Histone Deacetylase Inhibitors
  • Histones
  • Naphthalenes
  • Pyrones
  • Radiation-Sensitizing Agents
  • Transcription Factors
  • carboxycinnamic acid bishydroxamide
  • splitomicin
  • DNA
  • romidepsin
  • Histone Acetyltransferases
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Fluorouracil