Genetic dissection of histone deacetylase requirement in tumor cells
Genetic dissection of histone deacetylase requirement in tumor cells
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DOI：
10.1073/pnas.0903139106
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发表时间：
2009-05-12
影响因子：
11.1
通讯作者：
Olson, Eric N.
中科院分区：
文献类型：
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作者：
Haberland, Michael;Johnson, Aaron;Olson, Eric N.
组蛋白去乙酰化酶抑制剂（HDACi）代表了一组新的药物，目前正在测试中的各种临床应用。它们在癌症的临床前模型中特别有效，其中它们在许多不同类型的癌细胞中显示出抗增殖作用。最近，第一个HDACi被批准用于治疗皮肤T细胞淋巴瘤。目前在临床开发中的大多数HDACi通过非特异性干扰所有I类HDAC（HDAC 1、2、3和8）的酶活性而起作用，并且人们普遍认为，异构体特异性HDACi的开发可以导致更好的治疗功效。然而，到目前为止，单个I类HDAC对不同疾病状态的贡献尚未完全阐明。在这里，我们使用遗传方法来剖析肿瘤细胞中不同I类HDAC的参与。我们发现，删除一个单一的HDAC是不足以诱导细胞死亡，但HDAC1和2发挥冗余和重要的作用，在肿瘤细胞的生存。它们的缺失导致核桥接、核碎裂和有丝分裂灾难，反映了HDACi对癌细胞的影响。这些发现表明，HDAC 1和2的药理学抑制可能足以产生抗癌活性，为开发亚型特异性HDAC抑制剂提供了实验框架。
Histone deacetylase inhibitors (HDACi) represent a new group of drugs currently being tested in a wide variety of clinical applications. They are especially effective in preclinical models of cancer where they show antiproliferative action in many different types of cancer cells. Recently, the first HDACi was approved for the treatment of cutaneous T cell lymphomas. Most HDACi currently in clinical development act by unspecifically interfering with the enzymatic activity of all class I HDACs (HDAC1, 2, 3, and 8), and it is widely believed that the development of isoform-specific HDACi could lead to better therapeutic efficacy. The contribution of the individual class I HDACs to different disease states, however, has so far not been fully elucidated. Here, we use a genetic approach to dissect the involvement of the different class I HDACs in tumor cells. We show that deletion of a single HDAC is not sufficient to induce cell death, but that HDAC1 and 2 play redundant and essential roles in tumor cell survival. Their deletion leads to nuclear bridging, nuclear fragmentation, and mitotic catastrophe, mirroring the effects of HDACi on cancer cells. These findings suggest that pharmacological inhibition of HDAC1 and 2 may be sufficient for anticancer activity, providing an experimental framework for the development of isoform- specific HDAC inhibitors.