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Chromatin Modulation by Histone Deacetylase Inhibitors: Impact on Cellular Sensitivity to Ionizing Radiation.

ABSTRACT: It is well established that cells are more sensitive to ionizing radiation during the G2/M phase of the cell cycle when their chromatin is highly compacted. However, highly compacted chromatin is less susceptible to DNA Double Strand Breaks (DSBs) than relaxed chromatin. Therefore, it is now becoming apparent that it is the cell capacity to repair its damaged DNA and refold its chromatin into its original compacted status that primarily affects the overall cellular sensitivity to ionizing radiation. The Histone Deacetylase Inhibitors (HDACIs) are a new class of anticancer agents that relax chromatin structure by increasing the levels of histone acetylation. The effect of HDACIs on normal and cancer cells sensitivity to ionizing radiation differs. Reports have indicated that HDACIs can protect normal cells while simultaneously sensitize cancer cells to ionizing radiation. This difference may stem from the individual characteristic of the normal and cancer cells chromatin structure. This review discusses this possibility and addresses the role of HDACIs in radiation therapy.

SUBMITTER: Carrier F

PROVIDER: S-EPMC3955893 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Chromatin Modulation by Histone Deacetylase Inhibitors: Impact on Cellular Sensitivity to Ionizing Radiation.

Carrier France F

Molecular and cellular pharmacology 20130101 1

It is well established that cells are more sensitive to ionizing radiation during the G<sub>2</sub>/M phase of the cell cycle when their chromatin is highly compacted. However, highly compacted chromatin is less susceptible to DNA Double Strand Breaks (DSBs) than relaxed chromatin. Therefore, it is now becoming apparent that it is the cell capacity to repair its damaged DNA and refold its chromatin into its original compacted status that primarily affects the overall cellular sensitivity to ioni ...[more]

PMID: 24648865

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Project description:BackgroundThe overexpression of histone deacetylase (HDAC) and a subsequent decrease in the acetylation levels of nuclear histones are frequently observed in cancer cells. Generally it was accepted that the deacetylation of histones suppressed expression of the attached genes. Therefore, it has been suggested that HDAC might contribute to the survival of cancer cells by altering the NKG2D ligands transcripts. By the way, the translational regulation of NKG2D ligands remains unclear in cancer cells. It appears the modulation of this unclear mechanism could enhance NKG2D ligand expressions and the susceptibility of cancer cells to NK cells. Previously, it was reported that irradiation can increase the surface expressions of NKG2D ligands on several cancer cell types without increasing the levels of NKG2D ligand transcripts via ataxia telangiectasia mutated and ataxia telangiectasia and Rad3 related (ATM-ATR) pathway, and suggested that radiation therapy might be used to increase the translation of NKG2D ligands.MethodsTwo NSCLC cell lines, that is, A549 and NCI-H23 cells, were used to investigate the combined effects of ionizing radiation and HDAC inhibitors on the expressions of five NKG2D ligands. The mRNA expressions of the NKG2D ligands were quantitated by multiplex reverse transcription-PCR. Surface protein expressions were measured by flow cytometry, and the susceptibilities of cancer cells to NK cells were assayed by time-resolved fluorometry using the DELFIA® EuTDA cytotoxicity kit and by flow cytometry.ResultsThe expressions of NKG2D ligands were found to be regulated at the transcription and translation levels. Ionizing radiation and HDAC inhibitors in combination synergistically increased the expressions of NKG2D ligands. Furthermore, treatment with ATM-ATR inhibitors efficiently blocked the increased translations of NKG2D ligands induced by ionizing radiation but did not block the increased ligand translations induced by HDAC inhibitors. The study confirms that increased NKG2D ligand levels by ionizing radiation and HDAC inhibitors could synergistically enhance the susceptibilities of cancer cells to NK-92 cells.ConclusionsThis study suggests that the expressions of NKG2D ligands are regulated in a complex manner at the multilevel of gene expression, and that their expressions can be induced by combinatorial treatments in lung cancer cells.

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Chromatin Modulation by Histone Deacetylase Inhibitors: Impact on Cellular Sensitivity to Ionizing Radiation.

Publications

Chromatin Modulation by Histone Deacetylase Inhibitors: Impact on Cellular Sensitivity to Ionizing Radiation.

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