The histone deacetylase inhibitor, trichostatin A, enhances radiation sensitivity and accumulation of γH2A.X

Tom C. Karagiannis, K. N. Harikrishnan, Assam El-Osta

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Histone deacetylase inhibitors have been shown to induce numerous biologic effects including, altering cell cycle distribution, cytostasis and in certain cases apoptosis. Given their ability to disrupt critical biological processes in cancer cells, these agents are emerging as potential therapeutics for cancer. Recently, it has been identified that histone deacetylase inhibitors can also efficiently enhance the radiation sensitivity of cells, both in vitro and in vivo. In this study, we investigated whether the potent histone deacetylase inhibitor, Trichostatin A, modulates the radiation sensitivity of human erythroleukemic K562 cells. The endpoints we used were clonogenic survival, apoptosis and γH2AX immunoprecipitations of soluble chromatin. The findings from clonogenic survival assays indicated that incubation with Trichostatin A 24 hours prior to irradiation enhances the radiation sensitivity of K562 cells. The dose modification factors ranged from 1.1 when cells were incubated with 0.1 μM Trichostatin A to 2.3 at 1 μM Trichostatin A. Similarly, caspase-3 and caspase-7 assays indicated that Trichostatin A potentiates radiation-induced apoptosis in K562 cells, in a concentration dependent manner. Our results suggest the modulation of radiation effects observed at the lower Trichostatin A concentrations was associated with histone hyperacetylation and changes in phosphorylated γH2A.X formation on euchromatin. In contrast, at the higher Trichostatin A concentrations mechanisms such as drug-mediated cytotoxicity and G1 cell cycle arrest, contributed to the sensitization effect. More generally, our findings are consistent with those from recent studies and support the development of histone deacetylase inhibitors for use as radiation sensitizers, particularly for targeting radioresistant cancers.

Original languageEnglish
Pages (from-to)787-793
Number of pages7
JournalCancer Biology and Therapy
Volume4
Issue number7
DOIs
Publication statusPublished - 1 Jan 2005

Keywords

  • Chromatin remodeling
  • Histone acetylation
  • Histone deacetylase inhibitor
  • Radiosensitivity
  • Radiosensitizer
  • Trichostatin A
  • γH2A.X

Cite this

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title = "The histone deacetylase inhibitor, trichostatin A, enhances radiation sensitivity and accumulation of γH2A.X",
abstract = "Histone deacetylase inhibitors have been shown to induce numerous biologic effects including, altering cell cycle distribution, cytostasis and in certain cases apoptosis. Given their ability to disrupt critical biological processes in cancer cells, these agents are emerging as potential therapeutics for cancer. Recently, it has been identified that histone deacetylase inhibitors can also efficiently enhance the radiation sensitivity of cells, both in vitro and in vivo. In this study, we investigated whether the potent histone deacetylase inhibitor, Trichostatin A, modulates the radiation sensitivity of human erythroleukemic K562 cells. The endpoints we used were clonogenic survival, apoptosis and γH2AX immunoprecipitations of soluble chromatin. The findings from clonogenic survival assays indicated that incubation with Trichostatin A 24 hours prior to irradiation enhances the radiation sensitivity of K562 cells. The dose modification factors ranged from 1.1 when cells were incubated with 0.1 μM Trichostatin A to 2.3 at 1 μM Trichostatin A. Similarly, caspase-3 and caspase-7 assays indicated that Trichostatin A potentiates radiation-induced apoptosis in K562 cells, in a concentration dependent manner. Our results suggest the modulation of radiation effects observed at the lower Trichostatin A concentrations was associated with histone hyperacetylation and changes in phosphorylated γH2A.X formation on euchromatin. In contrast, at the higher Trichostatin A concentrations mechanisms such as drug-mediated cytotoxicity and G1 cell cycle arrest, contributed to the sensitization effect. More generally, our findings are consistent with those from recent studies and support the development of histone deacetylase inhibitors for use as radiation sensitizers, particularly for targeting radioresistant cancers.",
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The histone deacetylase inhibitor, trichostatin A, enhances radiation sensitivity and accumulation of γH2A.X. / Karagiannis, Tom C.; Harikrishnan, K. N.; El-Osta, Assam.

In: Cancer Biology and Therapy, Vol. 4, No. 7, 01.01.2005, p. 787-793.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Harikrishnan, K. N.

AU - El-Osta, Assam

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