Interferon regulatory factor-8 is important for histone deacetylase inhibitor-mediated antitumor activity.
Interferon regulatory factor-8 is important for histone deacetylase inhibitor-mediated antitumor activity.
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DOI：
10.1371/journal.pone.0045422
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Abrams SI
中科院分区：
文献类型：
--
作者：
Banik D;Khan AN;Walseng E;Segal BH;Abrams SI
肿瘤形成中的表观遗传改变是可逆的这一概念为鉴定表观遗传修饰剂诱导或增强肿瘤细胞死亡的能力提供了理论基础。组蛋白去乙酰化酶抑制剂（HDACi）代表这样一类抗肿瘤剂。尽管对临床应用很感兴趣，但关于对基于HDACi的癌症治疗反应重要的分子靶点知之甚少。我们先前已经表明，干扰素调节因子（IRF）-8，最初发现作为一个白血病抑制基因，通过调节细胞凋亡，也调节Fas介导的杀伤在非血液肿瘤模型。此外，我们和其他人已经表明，表观遗传机制参与肿瘤中IRF-8的抑制。因此，在我们的临床前肿瘤模型中，我们测试了IRF-8表达对于响应基于HDACi的抗肿瘤活性很重要的假设。在大多数实验中，我们选择了泛HDACi，曲古抑菌素A（TSA），因为先前显示其恢复Fas对肿瘤细胞的敏感性。总体而言，我们发现：1）TSA单独或与IFN-γ联合使用均能增强IRF-8表达和Fas介导的肿瘤细胞死亡; 2）TSA处理通过STAT 1依赖性途径增强IRF-8启动子活性;和3）IRF-8是这种死亡反应所必需的，由于使IRF-8丧失功能的肿瘤细胞对Fas介导的体外杀伤和HDACi的敏感性显著降低，介导的体内抗肿瘤活性。因此，IRF-8状态可能是HDACi抗肿瘤治疗反应的新分子基础。
The notion that epigenetic alterations in neoplasia are reversible has provided the rationale to identify epigenetic modifiers for their ability to induce or enhance tumor cell death. Histone deacetylase inhibitors (HDACi) represent one such class of anti-neoplastic agents. Despite great interest for clinical use, little is known regarding the molecular targets important for response to HDACi-based cancer therapy. We had previously shown that interferon regulatory factor (IRF)-8, originally discovered as a leukemia suppressor gene by regulating apoptosis, also regulates Fas-mediated killing in non-hematologic tumor models. Furthermore, we and others have shown that epigenetic mechanisms are involved in repression of IRF-8 in tumors. Therefore, in our preclinical tumor model, we tested the hypothesis that IRF-8 expression is important for response to HDACi-based antitumor activity. In the majority of experiments, we selected the pan-HDACi, Trichostatin A (TSA), because it was previously shown to restore Fas sensitivity to tumor cells. Overall, we found that: 1) TSA alone and more so in combination with IFN-γ enhanced both IRF-8 expression and Fas-mediated death of tumor cells in vitro; 2) TSA treatment enhanced IRF-8 promoter activity via a STAT1-dependent pathway; and 3) IRF-8 was required for this death response, as tumor cells rendered IRF-8 incompetent were significantly less susceptible to Fas-mediated killing in vitro and to HDACi-mediated antitumor activity in vivo. Thus, IRF-8 status may underlie a novel molecular basis for response to HDACi-based antitumor treatment.
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