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

通过表观遗传学机制的调节开发新的抗癌疗法

• 批准号: 17590273
• 负责人: ADACHI Masaaki
• 金额: $ 2.24万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590273/
• 关键词: Histone acetylation; apoptosis; mitochondria; ROS; DNA damage; chromatin; JNK

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.

为了建立一种新的抗癌疗法，我们研究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节。染色质结构的改变广泛地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，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JNK活化和随后的DSB增加来增强放射敏感性。抗癌疗法。

项目成果

Sulindac enhances the proteasome inhibitor bortezomib-mediated oxidative stress and anticancer activity

• DOI: 10.1158/1078-0432.ccr-05-0085
• 发表时间: 2005-07-15
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Minami, T;Adachi, M;Imai, K
• 通讯作者: Imai, K

2-Methoxye ol, an Endogenous Mammalian Metabolite,Radiosensitizes Colon Carcinoma Cells through c-Jun N-Terminal kinase Activation

2-Methoxye ol 是一种内源性哺乳动物代谢物，通过 c-Jun N 端激酶激活使结肠癌细胞放射增敏

• 发表时间: 2006
• 期刊: Clinical Cancer Res. 12
• 作者: Greimel;P;HuiChao Zou
• 通讯作者: HuiChao Zou

Bmf is a possible mediator in HDAC inhibitors FK228 and CBHA-induced apoptosis

Bmf 可能是 HDAC 抑制剂 FK228 和 CBHA 诱导的细胞凋亡的介质

• 发表时间: 2006
• 期刊: Cell Death Differ 13
• 作者: Fujimura;S.;et al.;Yubin Zhang
• 通讯作者: Yubin Zhang

Adenovirus-mediated gene transfer of caspase-8 sensitizes human adenocarcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand.

• DOI: 10.3892/ijo.26.2.537
• 发表时间: 2005-02
• 期刊: International journal of oncology
• 影响因子: 5.2
• 作者: H. Yasui;M. Adachi;H. Hamada;K. Imai

Bmf contributes to histone deacetylase inhibitor-mediated enhancing effects on apoptosis after ionizing radiation

• DOI: 10.1007/s10495-006-8266-1
• 发表时间: 2006-08-01
• 期刊: APOPTOSIS
• 影响因子: 7.2
• 作者: Zhang, Yubin;Adachi, Masaaki;Shinomura, Yasuhisa
• 通讯作者: Shinomura, Yasuhisa