Development of a new anticancer therapy by reguration of machinery for epigenetics

为了建立一种新的抗癌治疗方法，我们研究了组蛋白结构的修饰是否可以增强放射敏感性。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。染色质结构的改变广泛影响转录活性和对许多促凋亡刺激的敏感性。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损伤的影响，即双链DNA断裂（DSB），这可以通过组蛋白H2AX磷酸化来评估。我们还研究了bh3蛋白Bmf诱导是否对HDAC抑制剂介导的放射增强至关重要。从这些研究中，我们得到了以下结果：HDAC抑制剂能强烈诱导Bmf表达，增强放射敏感性。HDAC抑制剂介导的放射增强是由DSB.3的大量增加引起的。Bmf的诱导对于HDAC抑制剂介导的细胞凋亡和放射增强活性至关重要。4.2- me还通过JNK激活和随后DSB的增加来增强放射敏感性。这些数据表明，组蛋白修饰有助于开发新的抗癌疗法。

To establish a new anticancer therapy, we investigate whether modification of histone structure may enhance radiosensitivity. Histone acetylation is dynamically regulated by histone deacetylase (HDAC) and histone acetylation enzymes. Alternation of the chromatin structure extensively affects transcription activity, and susceptibility to many proapoptotic stimuli. 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 is useful for development of new anticancer therapies.