Adenovirus 5 E1A enhances histone deacetylase inhibitors-induced apoptosis through Egr-1-mediated Bim upregulation.
Adenovirus 5 E1A enhances histone deacetylase inhibitors-induced apoptosis through Egr-1-mediated Bim upregulation.
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DOI：
10.1038/onc.2010.295
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发表时间：
2010-10-14
期刊：
影响因子：
8
通讯作者：
Hung, M-C
中科院分区：
文献类型：
--
作者：
Yamaguchi, H.;Chen, C-T;Chou, C-K;Pal, A.;Bornmann, W.;Hortobagyi, G. N.;Hung, M-C
组蛋白脱乙酰酶抑制剂 (HDACi) 是针对多种癌症类型的有效抗癌药物。辛二酰苯胺异羟肟酸（SAHA）已被批准作为治疗皮肤T细胞淋巴瘤的药物，HDACi与其他药物的组合已在许多临床试验中得到积极测试。腺病毒 5 早期区域 1A (E1A) 已被证明具有高肿瘤抑制活性，并且使用 E1A 的基因治疗已在临床试验中进行了测试。在这里，我们发现 E1A 在多种癌细胞中显着增强 HDACi 的促凋亡活性，但在正常细胞中则不然。此外，我们还发现，E1A基因疗法与SAHA的组合在体内卵巢和乳腺异种移植模型中显示出高疗效和低毒性。 SAHA 下调 Bcl-XL 并上调促凋亡 BH3 蛋白 Bim，其表达在癌细胞中被 E1A 进一步增强。 Bcl-2 家族蛋白的这些改变对于癌细胞中组合诱导的细胞凋亡至关重要。 SAHA 增强 Bim 启动子区组蛋白 H3 的乙酰化，而 E1A 上调 Egr-1，直接参与 Bim 反式激活。总之，我们的结果不仅为 E1A 抗肿瘤活性的潜在机制提供了新的见解，而且为未来临床试验中 HDACi 和 E1A 基因联合治疗提供了理论依据。
Histone deacetylase inhibitors (HDACi) are potent anti-cancer agents for variety of cancer types. Suberoylanilide hydroxamic acid (SAHA) has been approved as a drug to treat cutaneous T cell lymphoma, and the combination of HDACi and other agents have been actively tested in many clinical trials. Adenovirus 5 early region 1A (E1A) has been shown to exhibit high tumor suppressor activity, and gene therapy using E1A has been tested in clinical trials. Here, we showed that proapoptotic activity of HDACi was robustly enhanced by E1A in multiple cancer cells, but not in normal cells. Moreover, we showed that combination of E1A gene therapy and SAHA showed high therapeutic efficacy with low toxicity in vivo ovarian and breast xenograft models. SAHA downregulated Bcl-XL and upregulated proapoptotic BH3-only protein Bim, whose expression was further enhanced by E1A in cancer cells. These alterations of Bcl-2 family proteins were critical for apoptosis induced by the combination in cancer cells. SAHA enhanced acetylation of histone H3 in Bim promoter region, while E1A upregulated Egr-1, which was directly involved in Bim transactivation. Together, our results provide not only a novel insight into the mechanisms underlying anti-tumor activity of E1A, but also a rationale for the combined HDACi and E1A gene therapy in future clinical trials.
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影响因子：
4.6
作者：
Chou, Chao-Kai;Lee, Dung-Fang;Sun, Hui-Lung;Li, Long-Yuan;Lin, Chun-Yi;Huang, Wei-Chien;Hsu, Jung-Mao;Kuo, Hsu-Ping;Yamaguchi, Hirohito;Wang, Ying-Nai;Liu, Mo;Wu, Hsin-Yi;Liao, Pao-Chi;Yen, Chia-Jui;Hung, Mien-Chie
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通讯作者：
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影响因子：
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作者：
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通讯作者：
HOUSMAN, DE