Targeting Transcriptional Co-repressor CoREST Complex in Melanoma

由染色质结构变化介导的基因转录模式的精确控制对于细胞生长至关重要。 在癌细胞中被破坏的身份保留。CoREST复合物是一种多蛋白复合物， 组蛋白修饰酶，作为一种转录辅阻遏物，通过促进阻遏蛋白的形成， 染色质CoREST复合物包含两种关键的组蛋白修饰酶，赖氨酸特异性组蛋白 脱甲基酶1（LSD 1）和组蛋白脱乙酰酶1和2（HDAC 1和HDAC 2）通过CoREST保持在一起 支架蛋白这些酶通常在癌症中上调，这表明CoREST复合物是一种蛋白酶。 用于癌症治疗特异性靶点。这项拟议研究的目标是从分子上定义CoREST 作为癌症的治疗靶点。我们最近开发了一种小分子抑制剂（corin 2）， CorREST复合体。Corin 2是CoREST复合物中LSD 1和HDACs 1/2的双重抑制剂，并且显示出高的 当针对NCI 60面板进行筛选时，对许多癌细胞类型具有强效抗增殖作用， 对人黑色素瘤有特别的疗效。我们的初步数据表明， 激活c-MYC/E2 F刺激的与细胞周期进展和增殖相关的靶基因。在 相反，编码BMP/SMAD膜结合配体依赖性核受体的基因， 已知用于促进细胞分化的基因，被CoREST复合物转录沉默。反- TGF-β/BMP-介导的SMAD信号通路的增殖作用是有据可查的;然而， 在许多癌细胞中功能常常丧失。在这里，我们假设CoREST复合物诱导了破坏， BMP/SMAD驱动的抗增殖/分化信号导致增加的转录激活， MYC/E2 F依赖性增殖基因网络。通过这种方式，阻断CoREST/MYC增殖基因 转录网络电路有望成为治疗癌症的有效策略。为了验证这个假设，我们将 使用黑色素瘤作为靶癌症模型来实现以下目的：1）分析黑色素瘤的全基因组效应， corin 2发现CoREST复合物靶基因特征及其与c-MYC/E2 F靶的相关性 转录网络，2）定义BMP/SMAD信号传导中的CoREST复合物的作用，以及从转录网络的转换， 3）评估corin 2作为表观遗传表型， 通过靶向c-MYC/E2 F转录的转录调节机制的抗肿瘤剂 网络为了实现这些目标，我们将使用小分子CoREST抑制剂corin 2，以及一种 一系列化学相关的类似物;基因工程小鼠黑素瘤模型;和人黑素瘤 组织标本这些拟议的研究将扩大我们的知识染色质阻遏的CorREST 复合体及其在调节细胞增殖基因转录网络中的作用。因此，本提案 将提供一个机制的基本原理，为发展一种新的治疗策略，针对表观遗传 黑色素瘤和其他癌症的恶性相关途径。

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.