Molecular analysis of cross-talk between histone acetylation and radiation sensitivity

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Modification of histone structure may be associated with radiosensitivity. Based on this hypothesis, we investigated whether there is some correlation between histone acetylation and radiosensitivity. Histone acetylation is dynamically regulated by histone deacetylase (HDAC) and histone acetylation enzymes, and change the chromatin structure, which is crucial for transcription activation or gene silencing. We first investigated effect of several HDAC inhibitors on ionizing radiation (IR)-induced cell death in cancer cell lines. Next, we evaluated their effects on IR-induced DNA damage, namely double strand DNA break (DSB), which can be evaluated by histone H2AX phosphorylation. We also investigated if BH3-only protein Bmf induction is crucial for HDAC inhibitor-mediated radioenhancement. From these studies, we obtained following results.1.HDAC inhibitors induce Bmf expression strongly and enhance radiosensitivity.2.HDAC inhibitor-mediated radioenhancement is caused by a substantial increase of DSB.3.Bmf induction is crucial for the HDAC inhibitor-mediated apoptosis and radioenhancement activity.4.2-ME also enhances radiosensitivity by JNK activation and subsequent increase of DSB.These data indicate that histone modification can be a crucial factor to regulate radiosensitivity, and suggest that enhancement of histone acetylation may be one of the best ways to enhance radiosensitivity.