Histone deacetylase inhibitors induce cell death selectively in cells that Harbor activated kRasV12: The role of signal transducers and activators of transcription 1 and p21
Histone deacetylase inhibitors induce cell death selectively in cells that Harbor activated kRasV12: The role of signal transducers and activators of transcription 1 and p21
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DOI：
10.1158/0008-5472.can-07-0210
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发表时间：
2007-09-15
期刊：
影响因子：
11.2
通讯作者：
Augenlicht, Leonard
中科院分区：
文献类型：
--
作者：
Klampfer, Lidija;Huang, Jie;Augenlicht, Leonard
组蛋白脱乙酰酶 (HDAC) 抑制剂 (HDACi) 显示出有效且选择性的抗肿瘤活性，尽管它们会在正常细胞和肿瘤细胞中诱导历史性的高度乙酰化。在这项研究中，我们发现，未转化肠上皮细胞中 kRasV12 的诱导表达显着降低了线粒体膜电位 (MMP)，并使细胞对 HDACi 诱导的细胞凋亡敏感。与我们发现具有突变 Ras 的结肠癌细胞系降低了信号转导子和转录激活子 1 (STAT1) 的表达相一致，我们发现突变 Ras 的诱导表达显着降低了 STAT1（一种具有肿瘤抑制活性的转录因子）的基础表达和诱导表达。为了研究携带突变 Ras 的细胞中 STAT1 表达的减少是否导致其对 HDACi 的敏感性增加，我们用小干扰 RNA 沉默了 HKe-3 细胞中 STAT1 的表达。尽管 STAT1 的沉默不足以改变 MMP，但 STAT1 缺陷，如 Ras 突变，使细胞对 HDACi 诱导的细胞凋亡敏感。我们发现，在 STAT1 表达沉默的 HKe-3 细胞中，HDACi 对 p21 的诱导显着受损，并表明在 STAT1 缺陷的 HKe-3 细胞中，丁酸激活 p21 转录的能力减弱。最后，我们使用靶向删除 p21 的细胞来证实 p21 可以保护细胞免受丁酸盐诱导的细胞凋亡，这强烈表明在这些细胞中 STAT1 缺陷通过 p21 的诱导受损而促进丁酸盐诱导的细胞凋亡。因此，我们的数据表明，Ras 突变以及随之而来的 STAT1 表达减少是转化细胞响应 HDAC 活性抑制剂治疗而发生凋亡的敏感性增加的基础。
Histone deacetylase (HDAC) inhibitors (HDACi) show potent and selective antitumor activity despite the fact that they induce historic hyperacetylation in both normal and tumor cells. In this study, we showed that the inducible expression of kRasV12 in nontransformed intestinal epithelial cells significantly lowered the mitochondrial membrane potential (MMP) and sensitized cells to HDACi-induced apoptosis. Consistent with our finding that colon cancer cell lines with mutant Ras have reduced expression of signal transducers and activators of transcription 1 (STAT1), we showed that inducible expression of mutant Ras markedly decreased both basal and inducible expression of STAT1, a transcription factor with tumor suppressor activity. To investigate whether reduced expression of STAT1 in cells that harbor mutant Ras contributes to their increased sensitivity to HDACi, we silenced the expression of STAT1 in HKe-3 cells with small interfering RNA. Despite the fact that silencing of STAT1 was not sufficient to alter the MMP, STAT1 deficiency, like Ras mutations, sensitized cells to apoptosis induced by HDACi We showed that the induction of p21 by HDACi was significantly impaired in HKe-3 cells with silenced STAT1 expression and showed that the ability of butyrate to activate p21 transcription was diminished in STAT1-deficient HKe-3 cells. Finally, we used cells with targeted deletion of p21 to confirm that p21 protects cells from butyrate-induced apoptosis, strongly suggesting that in these cells STAT1 deficiency promotes butyrate-induced apoptosis through impaired induction of p21. Our data therefore establish that Ras mutations, and consequent reduction in the expression of STAT1, underlie the increased susceptibility of transformed cells to undergo apoptosis in response to treatment with inhibitors of HDAC activity.