Dipartimento di Patologia Generale, Seconda Università di Napoli, Naples, Italy.
J Mol Endocrinol. 2010 Oct;45(4):219-28. doi: 10.1677/JME-10-0043. Epub 2010 Jul 16.
Epigenetic deregulation contributes to diseases including cancer, neurodegeneration, osteodystrophy, cardiovascular defects, and obesity. For this reason, several inhibitors for histone deacetylases (HDACs) are being validated as novel anti-cancer drugs in clinical studies and display important anti-proliferative activities. While most inhibitors act on both class I, II, and IV HDACs, evidence is accumulating that class I is directly involved in regulation of cell growth and death, whereas class II members regulate differentiation processes, such as muscle and neuronal differentiation. Here, we show that the novel class II-selective inhibitor MC1568 interferes with the RAR- and peroxisome proliferator-activated receptor γ (PPARγ)-mediated differentiation-inducing signaling pathways. In F9 cells, this inhibitor specifically blocks endodermal differentiation despite not affecting retinoic acid-induced maturation of promyelocytic NB4 cells. In 3T3-L1 cells, MC1568 attenuates PPARγ-induced adipogenesis, while the class I-selective MS275 blocked adipogenesis completely thus revealing a different mode of action and/or target profile of the two classes of HDACs. Using in vivo reporting PPRE-Luc mice, we find that MC1568 impairs PPARγ signaling mostly in the heart and adipose tissues. These results illustrate how HDAC functions can be dissected by selective inhibitors.
表观遗传失调导致多种疾病，包括癌症、神经退行性疾病、骨营养不良、心血管缺陷和肥胖。出于这个原因，几种组蛋白去乙酰化酶（HDAC）抑制剂正在临床研究中被验证为新型抗癌药物，并显示出重要的抗增殖活性。虽然大多数抑制剂作用于 I 类、II 类和 IV 类 HDAC，但越来越多的证据表明 I 类直接参与细胞生长和死亡的调节，而 II 类成员调节分化过程，如肌肉和神经元分化。在这里，我们表明新型 II 类选择性抑制剂 MC1568 干扰 RAR 和过氧化物酶体增殖物激活受体 γ（PPARγ）介导的分化诱导信号通路。在 F9 细胞中，尽管该抑制剂不影响维甲酸诱导的早幼粒细胞 NB4 细胞的成熟，但它特异性地阻断内胚层分化。在 3T3-L1 细胞中，MC1568 减弱了 PPARγ 诱导的脂肪生成，而 I 类选择性抑制剂 MS275 则完全阻断了脂肪生成，从而揭示了两类 HDAC 的不同作用模式和/或靶标特征。使用体内报告 PPRE-Luc 小鼠，我们发现 MC1568 主要在心脏和脂肪组织中损害 PPARγ 信号。这些结果说明了如何通过选择性抑制剂来剖析 HDAC 功能。
