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

组蛋白结构的改变可能与放射敏感性有关。基于这一假设，我们研究了组蛋白乙酰化与辐射敏感性之间是否存在某种相关性。组蛋白乙酰化受组蛋白去乙酰化酶（HDAC）和组蛋白乙酰化酶的动态调控，改变染色质结构，对转录激活或基因沉默起着至关重要的作用。我们首先研究了几种HDAC抑制剂对电离辐射（IR）诱导的癌细胞系细胞死亡的影响。接下来，我们评估了它们对IR诱导的DNA损伤，即双链DNA断裂（DSB）的影响，这可以通过组蛋白H2 AX磷酸化来评估。我们还研究了BH 3-only蛋白Bmf诱导是否对HDAC转运蛋白介导的放射增强至关重要。从这些研究中，我们得到以下结果：1. HDAC抑制剂强烈诱导Bmf表达，并增强放射增敏作用; 2. HDAC受体介导的放射增敏作用是由DSB的大量增加引起的; 3. Bmf诱导对HDAC受体介导的凋亡和放射增敏作用至关重要。ME还通过激活JNK和随后增加DSB来增强辐射敏感性。这些数据表明，组蛋白修饰可能是调节辐射敏感性的关键因素。提示增强组蛋白乙酰化可能是增强放射敏感性的最佳途径之一。

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.