HDAC Inhibitors Disrupt Programmed Resistance to Apoptosis During Drosophila Development.
HDAC Inhibitors Disrupt Programmed Resistance to Apoptosis During Drosophila Development.
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DOI：
10.1534/g3.117.041541
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发表时间：
2017-06-07
期刊：
影响因子：
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通讯作者：
Bashirullah A
中科院分区：
文献类型：
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作者：
Kang Y;Marischuk K;Castelvecchi GD;Bashirullah A
我们之前已经证明，在果蝇的发育过程中，对凋亡触发因素的反应能力受到调节，有效地将果蝇的生命周期划分为对凋亡敏感或抗性的阶段。在这里，我们发现发育程序对凋亡的抗性涉及组蛋白去乙酰化酶（hdac）对关键促凋亡基因的转录抑制。给药HDAC抑制剂（HDACi），如曲古霉素A或亚酰苯胺羟肟酸，增加促凋亡基因的表达，足以使其他耐药阶段变得敏感。相反，降低促凋亡基因的水平会使细胞抵抗其他敏感阶段。鉴于抗凋亡是癌细胞的一个标志，并且HDACi最近被添加到fda批准的癌症治疗药物的列表中，我们的研究结果为HDACi如何帮助杀死恶性细胞提供了新的见解，同时也引起了人们对其对健康细胞潜在的意外影响的关注。
We have previously shown that the ability to respond to apoptotic triggers is regulated during Drosophila development, effectively dividing the fly life cycle into stages that are either sensitive or resistant to apoptosis. Here, we show that the developmentally programmed resistance to apoptosis involves transcriptional repression of critical proapoptotic genes by histone deacetylases (HDACs). Administration of HDAC inhibitors (HDACi), like trichostatin A or suberoylanilide hydroxamic acid, increases expression of proapoptotic genes and is sufficient to sensitize otherwise resistant stages. Conversely, reducing levels of proapoptotic genes confers resistance to otherwise sensitive stages. Given that resistance to apoptosis is a hallmark of cancer cells, and that HDACi have been recently added to the repertoire of FDA-approved agents for cancer therapy, our results provide new insights for how HDACi help kill malignant cells and also raise concerns for their potential unintended effects on healthy cells.