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Targeting Transcriptional Co-repressor CoREST Complex in Melanoma

靶向黑色素瘤中的转录辅阻遏物 CoREST 复合物

基本信息

批准号：
10221630
负责人：
Byungwoo Ryu
金额：
$ 39.87万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221630
关键词：
Animal Model Antineoplastic Agents Automobile Driving Biochemical Bioinformatics Cancer Model Cancer cell line Cell Cycle Cell Cycle Progression Cell Differentiation process Cell Line Cell Proliferation Cells ChIP-seq Chemicals Chromatin Chromatin Structure Cleaved cell Clinical Complex Data Development Down-Regulation E2F transcription factors Enzymes Epigenetic Process Evaluation Excision Flavins Gene Activation Gene Expression Profile Gene Expression Profiling Gene Silencing Genes Genetic Genetic Transcription Genetically Engineered Mouse Goals HDAC1 gene HDAC2 gene Histone Deacetylase Histone Deacetylase Inhibitor Histones Human Knowledge Ligands Lysine Malignant Neoplasms Manuscripts Mediating Melanoma Cell Membrane Mitogen-Activated Protein Kinases Modeling Molecular Molecular Target Multiprotein Complexes Mus Nature Nuclear Receptors Oncogenes Oxidases Pathway interactions Pattern Pharmacology Phenotype Post-Translational Protein Processing Repressor Proteins Role Scaffolding Protein Series Signal Pathway Signal Transduction Specificity Specimen Substrate Specificity Testing Tissues Transactivation Transcription Regulatory Protein Transcriptional Activation Transcriptional Regulation Transforming Growth Factor beta analog anti-cancer anticancer research antitumor agent antitumor effect base c-myc Genes cancer cell cell growth cell type comparative design epigenetic silencing genetic corepressor genetic signature genome analysis genome-wide genomic locus histone demethylase improved in vivo inhibitor/antagonist insight melanocyte melanoma neoplastic cell new therapeutic target novel therapeutic intervention preservation programs promoter screening small molecule small molecule inhibitor targeted agent targeted cancer therapy therapeutic target transcriptome tumor tumor growth

项目摘要

Precise control of gene transcription patterns, mediated by chromatin structural changes, is essential for cell identity preservation that is disrupted in cancer cells. The CoREST complex, a multi-protein complex of histone-modifying enzymes, functions as a transcriptional co-repressor by facilitating formation of repressive chromatin. The CoREST complex contains two key histone modifying enzymes, lysine-specific histone demethylase 1 (LSD1) and histone deacetylase 1 and 2 (HDAC1 and HDAC2) held together by the CoREST scaffolding protein. These enzymes are typically up-regulated in cancer, suggesting the CoREST complex is a specific target for cancer therapy. The goal of this proposed study is to molecularly define the CoREST complex as a therapeutic target for cancer. We recently developed a small molecule inhibitor (corin2) of the CoREST complex. Corin2 is a dual inhibitor of LSD1 and HDACs1/2 in the CoREST complex and shows high potency anti-proliferative effects against many cancer cell types when screened against the NCI 60 panel, with particular efficacy versus human melanomas. Our preliminary data suggests that the CoREST complex activates c-MYC/E2F-stimulated target genes associated with cell cycle progression and proliferation. In contrast, genes encoding the BMP/SMAD membrane-bound ligand-dependent nuclear receptors, which are known for promoting cellular differentiation, are transcriptionally silenced by the CoREST complex. The anti- proliferative role of the TGF-β/BMP-mediated SMAD signaling pathway is well documented; however, this function is often lost in many cancer cells. Here, we hypothesize that the CoREST complex induces disruption of BMP/SMAD driven anti-proliferative/differentiation signals resulting in increased transcriptional activation of the MYC/E2F-dependent proliferation gene network. In this way, blocking the CoREST/MYC proliferative gene transcription network circuit is expected to be an effective strategy in cancer. To test this hypothesis, we will perform the following aims using melanoma as a target cancer model: 1) analyze genome-wide effects of corin2 to discover the CoREST complex target gene signature and its correlation with the c-MYC/E2F target transcription network, 2) define the role of the CoREST complex in BMP/SMAD signaling and the switch from a differentiation/tumor- suppressive phenotype to cell growth phenotype, 3) evaluate corin2 as an epigenetic anti-tumor agent by targeting the transcriptional regulatory mechanisms of the c-MYC/E2F transcription network. To accomplish these aims, we will use the small molecule CoREST inhibitor, corin2, as well as a series of chemically-related analogs; a genetically engineered mouse melanoma model; and human melanoma tissue specimens. These proposed studies will extend our knowledge of the chromatin repressive CoREST complex and its roles in regulating a cell proliferative gene transcription network. In this manner, this proposal will provide a mechanistic rationale for the development of a novel therapeutic strategy targeting epigenetic malignancy-associated pathways in melanoma and other cancers.

由染色质结构变化介导的基因转录模式的精确控制对细胞是至关重要的。在癌细胞中被破坏的身份保留。核心复合体，一种多蛋白复合体组蛋白修饰酶通过促进抑制物的形成而起到转录辅助抑制物的作用染色质。核心复合体包含两个关键的组蛋白修饰酶，赖氨酸专一性的组蛋白去甲基酶1(LSD1)和组蛋白脱乙酰酶1和2(HDAC1和HDAC2)被核心结合在一起支架蛋白。这些酶在癌症中通常上调，这表明核心复合体是一种癌症治疗的特定靶点。这项拟议的研究的目标是从分子上定义核心层作为癌症治疗靶点的复合体。我们最近开发了一种小分子抑制剂(Corin2)。岩心复合体。Corin2是核心区复合体中LSD1和HDACs1/2的双重抑制剂，表现出很高的当与NCI 60小组进行筛选时，针对许多类型的癌细胞具有抗增殖的效力，对人类黑色素瘤的特殊疗效。我们的初步数据显示，岩心复合体激活c-myc/E2F刺激的与细胞周期进展和增殖相关的靶基因。在……里面相比之下，编码BMP/SMAD膜结合配体依赖的核受体的基因以促进细胞分化而闻名，被核心复合体转录沉默。反- 转化生长因子-β/骨形态发生蛋白介导的SMAD信号通路的增殖作用已得到很好的证实；然而，这许多癌细胞的功能经常丧失。在这里，我们假设岩心复合体诱导了分裂 BMP/SMAD驱动的抗增殖/分化信号导致转录激活增加依赖MYC/E2F的增殖基因网络。通过这种方式，阻断COREST/MYC增殖基因转录网络回路有望成为肿瘤治疗的有效策略。为了检验这一假设，我们将使用黑色素瘤作为靶肿瘤模型来实现以下目标：1)分析全基因组的影响 Corin2发现核心复合体靶基因特征及其与c-myc/E2F靶基因的相关性转录网络，2)确定核心复合体在BMP/SMAD信号转导中的作用以及从分化/肿瘤抑制表型到细胞生长表型，3)评价Corin2作为表观遗传学靶向c-myc/E2F转录调控机制的抗肿瘤药物网络。为了实现这些目标，我们将使用小分子核心抑制物corin2以及一系列化学相关类似物；基因工程小鼠黑色素瘤模型；以及人类黑色素瘤组织标本。这些拟议的研究将扩展我们对染色质抑制核心的了解复合体及其在调节细胞增殖基因转录网络中的作用。如此一来，这项提案将为以表观遗传学为靶点的新治疗策略的开发提供机制基础黑色素瘤和其他癌症中的恶性肿瘤相关途径。