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 表观遗传重塑越来越被认为是癌变的驱动力和有前途的药物靶标 癌症治疗。组蛋白脱乙酰基酶抑制剂（HDI）是最突出的表观遗传药物之一 在500多个临床试验中对各种癌症进行了测试，并具有两种已经批准的化合物。尽管他们 普遍的抗癌效率，其作用机理尚不清楚。目前假定通过抑制 组蛋白脱乙酰基酶（HDAC），HDI改变了与细胞生长或存活有关的基因的表达。但是，基因 HDI-WERAT细胞的表达分析表明，不同HDI之间的变化最小和不同的模式。 许多HDAC，包括HDAC1、2、3、6及其相关的转录组合剂，已证明 充当肿瘤补充剂。显然，关于HDIS的工作方式有一定差距。我们最近的发现 挑战HDI的当前观点。我们发现，HDAC3的肝特异性敲除上调脂肪生成靶 基因和引起肝脂肪变性，这两者都可以通过HDAC3的酶死亡突变体挽救。我们 进一步发现，HDI不会上调靶基因目的地，导致组蛋白高乙酰化。这样的 酶活性和HDAC函数之间的解离问题质疑HDAC是否实际上是HDI的目标， 特别是考虑到HDAC3负责IIA级HDACS的酶活性（HDAC4、5、7和 9）不具有固有的催化活性。 HDACS的视图作为癌基因也与其肿瘤不一致 抑制剂在视网膜细胞瘤蛋白和雌激素/雄激素受体信号通路中的作用。 HDI是 旨在珍惜HDACS3催化口袋中的锌离子，因此可以针对数百个其他 锌依赖性金属蛋白。我们假设非HDAC蛋白实际上是HDI的靶标 抗癌效率。我们将通过确定是否需要HDAC酶活性来检验假设 细胞对HDI的反应；表征HDI相互作用的非HDAC蛋白在抗癌作用中的作用 hdis;并确定HDAC酶活性在肝癌发生和对HDI的肝反应中的作用 体内。我们的假设，如果被证明是正确的，那将是概念上的进步，它将彻底改变我们的发展战略 这些有希望的抗癌药。我们的研究还直接检验了“组蛋白代码”假设 哺乳动物中前所未有的量表，并将对表观遗传学和基因转录领域产生广泛的影响 规定。