De facto Target of Histone Deacetylase Inhibitors

组蛋白脱乙酰酶抑制剂的事实上的靶点

• 批准号: 9296286
• 负责人: Zheng Sun
• 金额: $ 17.24万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296286
• 关键词: Ablation; Address; Adenovirus Vector; Androgen Receptor; Antineoplastic Agents; Biological Assay; CRISPR library; Candidate Disease Gene; Cell Proliferation; Cell Survival; Cells; Chelating Agents; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Complementary DNA; Computer Simulation; Deacetylase; Dependovirus; Development; Dissociation; Drug Targeting; Enzymes; Epigenetic Process; Estrogens; Fatty Liver; Gene Expression; Gene Expression Profiling; Gene Targeting; Genetic Transcription; Guide RNA; HDAC1 gene; HDAC3 gene; HDAC4 gene; Hepatic; Hepatocarcinogenesis; Histology; Histone Code; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Image; Ions; Knock-in; Knock-out; Knowledge; Liver; Malignant Neoplasms; Mammals; Mediating; Metalloproteins; Mus; Oncogenes; Pattern; Primary carcinoma of the liver cells; Proteins; Receptor Signaling; Resistance; Retinoblastoma Protein; Role; SV40 T Antigens; Series; Signal Pathway; Silent Mutation; Subfamily lentivirinae; Testing; Transcriptional Regulation; Tumor Suppressor Proteins; Western Blotting; Work; Zinc; activity-based protein profiling; adenovirus mediated delivery; base; cancer cell; carcinogenesis; cell growth; chemoproteomics; design; enzyme activity; epigenetic drug; genome-wide analysis; in vivo; mutant; overexpression; reconstitution; resistance gene; response; targeted cancer therapy; tumor

SUMMARY/ABSTRACT Epigenetic remodeling is increasingly recognized as a driver of carcinogenesis and a promising drug target for cancer therapy. Histone deacetylase inhibitors (HDIs) are among the most prominent epigenetic drugs being tested in over 500 clinical trials against a variety of cancers with two compounds already approved. Despite their universal anticancer efficacy, their mechanism of action is not clear. It is currently assumed that, by inhibiting histone deacetylase (HDAC), HDIs alter expression of genes involved in cell growth or survival. However, gene expression profiling of HDI-treated cells revealed minimal changes and distinct patterns among different HDIs. Many HDACs, including HDAC1, 2, 3, 6, and their associated transcriptional coregulators, have been shown to function as tumor suppressors. There is clearly a gap of knowledge on how HDIs work. Our recent findings challenge the current view of HDIs. We found that liver-specific knockout of HDAC3 upregulates lipogenic target genes and causes hepatic steatosis, both of which can be rescued by enzyme-dead mutants of HDAC3. We further found that HDIs do not upregulate target genes despite causing histone hyperacetylation. Such dissociation between enzyme activity and HDAC function questions whether HDAC is de facto target of HDI, especially considering that HDAC3 is responsible for the enzyme activity of class IIa HDACs (HDAC4, 5, 7, and 9) that do not possess intrinsic catalytic activity. The view of HDACs as oncogene is also at odds with their tumor suppressor role in retinoblastoma protein and estrogen/androgen receptor signaling pathways. HDIs are designed to chelate the zinc ion in the catalytic pocket of HDACs3, and therefore could target hundreds of other zinc-dependent metalloproteins. We hypothesize that non-HDAC proteins are de facto targets of HDI for its anticancer efficacy. We will tests the hypothesis by determining whether HDAC enzymatic activity is required for cellular response to HDIs; characterizing the role of HDI-interacting non-HDAC proteins in anticancer effects of HDIs; and determining the role HDAC enzymatic activity in liver carcinogenesis and hepatic response to HDIs in vivo. Our hypothesis, if proven correct, is a conceptual advance that will revolutionize our strategy in development of these promising anticancer drugs. Our study also directly tests the ‘histone code’ hypothesis on an unprecedented scale in mammals, and will have broad impact in the field of epigenetics and gene transcriptional regulation.

摘要/摘要 表观遗传重塑日益被认为是癌症发生的驱动因素和有望成为治疗癌症的药物靶点 癌症治疗。组蛋白脱乙酰酶抑制剂(HDI)是最突出的表观遗传药物之一 在500多项针对各种癌症的临床试验中进行了测试，其中两种化合物已经获得批准。尽管他们 普遍的抗癌功效，其作用机制尚不清楚。目前的假设是，通过抑制 组蛋白脱乙酰酶(HDAC)，HDI改变与细胞生长或生存有关的基因的表达。然而，基因 HDI处理的细胞的表达谱显示了不同HDI之间最小的变化和不同的模式。 许多HDACs，包括HDAC1、2、3、6和它们相关的转录辅助调节因子，已经被证明是 发挥肿瘤抑制因子的作用。关于人类发展指数是如何运作的，显然存在知识差距。我们最新的发现 挑战当前对人类发展指数的看法。我们发现肝脏特异的HDAC3基因敲除上调了成脂靶点 基因和导致肝脏脂肪变性，这两种疾病都可以通过HDAC3的酶死亡突变来挽救。我们 进一步发现，HDI不会上调靶基因，尽管会导致组蛋白超乙酰化。是这样的 酶活性和HDAC功能之间的分离质疑HDAC是否是HDI的实际靶标， 尤其是考虑到HDAC3负责IIa类HDAC(HDAC4、5、7和 9)不具有本征催化活性的。HDAC作为癌基因的观点与其肿瘤也是不一致的 在视网膜母细胞瘤蛋白和雌激素/雄激素受体信号通路中的抑制作用。HDI是 旨在螯合HDACs3催化口袋中的锌离子，因此可以针对数百种其他 依赖锌的金属蛋白。我们假设非HDAC蛋白实际上是HDI的靶标。 抗癌功效。我们将通过确定是否需要HDAC酶活性来检验这一假设 细胞对HDI的反应；鉴定HDI相互作用的非HDAC蛋白在抗癌作用中的作用 HDIs；以及测定HDAC酶活性在肝癌发生和肝脏对HDIs反应中的作用 活着。如果我们的假设被证明是正确的，那将是一个概念性的进步，它将彻底改变我们的发展战略 这些前景看好的抗癌药物。我们的研究还直接测试了组蛋白密码假说 哺乳动物中前所未有的规模，并将在表观遗传学和基因转录领域产生广泛影响 监管。