Pathogenesis and Treatment of NUT-Midline Carcinoma

NUT-中线癌的发病机制和治疗

• 批准号: 10407464
• 负责人: Christopher A French
• 金额: $ 33.33万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407464
• 关键词: Binding; Bromodomain; Carcinoma; Cells; Chromatin; Chromatin Loop; Complex; DNA; Development; Differentiated Gene; Disease; Dose-Limiting; EP300 gene; Enhancers; Enrollment; Genes; Genetic Transcription; Genomics; Goals; Growth; Histone Deacetylase; Histones; Lysine; Malignant Epithelial Cell; Malignant Neoplasms; Modeling; Molecular Conformation; Nuts; Oncogenes; Oncoproteins; Pathogenesis; Pathologic; Patients; Principal Investigator; Proteins; Recruitment Activity; Role; Seeds; Solid Neoplasm; Squamous cell carcinoma; Structure; Structure-Activity Relationship; Testing; Transferase; Up-Regulation; cell type; chromatin remodeling; inhibitor; mimetics; novel; novel therapeutics; prevent; programs; protein complex; recruit; therapeutic target; therapeutically effective; tumorigenesis; zinc finger nuclease

Project Summary Abstract. NUT midline carcinoma (NMC), with a median survival of 6.7 months, is one of the most aggressive solid tumors known. It is a subtype of squamous cell carcinoma characterized by translocation of the NUT (aka NUTM1) gene, most commonly forming a fusion to the double-bromodomain encoding protein (BET), BRD4. There is an urgent need for the identification of more specific therapeutic targets in NMC. The over-reaching goal of this proposed project is to greater understand the mechanism of BRD4-NUT oncogenesis and identify effective therapeutic targets for treating this disease. BRD4-NUT functions to block differentiation and maintain proliferation of NMC cells, largely through activation of MYC expression. This function is disrupted upon treatment with BET inhibitors, which as acetyl- lysine mimetics prevent binding of BRD4 bromodomains to acetylated chromatin. BRD4-NUT drives the expression of pro-growth target genes, including MYC, through the formation of megabase-sized massive hyperacetylated 'megadomains'. BRD4-NUT megadomains arise from pre-existing active enhancers and spread to fill cell-type-specific topologically associating domains (TADs). TADs are higher order genomic structures whose function is to orchestrate cell-fate determining transcriptional programs through DNA-DNA contacts. Unique proteins recruited by BRD4-NUT recently identified by our group include the histone acetyl- transferase (HAT), p300, and several ZNF proteins collectively termed Z4. These findings indicate that BRD4- NUT ‘hijacks’ cell-type specific TADs to drive transcription of pro-growth, anti-differentiative genes as postulated in the following model: First, BRD4-NUT complex proteins seed regions corresponding to cell-type- specific active TADs through the chromatin-binding of BRD4. Second, megadomains form from contiguous expansion of BRD4-NUT complexes across chromatin in a feed-forward manner dependent upon p300 HAT activity. Third, megadomain size is limited by TAD boundaries and HDAC activity recruited by the Z4 complex. Fourth, hyperacetylated chromatin, recruitment of chromatin remodelers, and upregulation of cis lncRNAs changes the chromatin configuration to enhance DNA-DNA interactions to drive transcription of key pro- growth, anti-differentiative genes. The goals of this proposal are to test this hypothetical model, as listed in the specific aims below. Aim 1. To determine how BRD4-NUT megadomains form. Aim 2. To determine how BRD4-NUT megadomains function. Impact. Successful completion of the aims is expected to identify key BRD4-NUT-associated proteins in pathologic megadomain formation, and will identify novel and possibly more effective therapeutic targets in NMC and other cancers. In addition, we predict that BRD4-NUT megadomains will provide a model with far- reaching impact on the structure-function relationship of chromatin conformation in cancer and development.

项目摘要摘要。中线癌（NMC）中位生存期为6.7个月，是一种 已知最具侵略性的实体瘤。它是鳞状细胞癌的亚型，其特征是 螺母（又称Nutm1）基因的转运，最常见的是与双溴a子形成融合 编码蛋白质（BET），BRD4。迫切需要鉴定更具体的疗法 NMC中的目标。该提议的项目的过度学习目标是更深入地了解 BRD4-NUT肿瘤发生并确定治疗该疾病的有效治疗靶标。 BRD4-NUT功能以阻止分化并维持NMC细胞的增殖，很大程度上通过 MYC表达的激活。通过用BET抑制剂治疗，该功能被破坏，该抑制剂作为乙酰基 - 赖氨酸模拟物可阻止BRD4溴结构域与乙酰化染色质结合。 brd4-nut驱动着 通过形成巨型大质量的大质量，包括MYC在内的促增长靶基因的表达 过度乙酰化的“巨大”。 Brd4-nut megadomains是由现有的活跃增强剂和 扩散以填充细胞类型特异性拓扑结合域（TADS）。 TAD是高阶基因组 其功能是编排细胞命令的结构，以确定通过DNA-DNA的转录程序 联系人。 BRD4-NUT募集的独特蛋白质最近由我们组确定的包括组蛋白乙酰基 - 转移酶（HAT），P300和几种ZNF蛋白统称为Z4。这些发现表明BRD4- 螺母“劫持”细胞类型的特定TAD，以驱动促生长，抗差异基因的转录 发表在以下模型中：首先，BRD4-NUT复合蛋白种子区域与细胞类型相对应 特定的活性TAD通过BRD4的染色质结合。其次，连续的大型群形成 以馈送方式延伸Brd4-nut复合物在染色质上的膨胀方式取决于P300 HAT 活动。第三，大型群的大小受Z4综合体募集的TAD边界和HDAC活动的限制。 第四，高乙酰化染色质，募集染色质重塑和CIS LNCRNA的上调 更改染色质构型以增强DNA-DNA相互作用以驱动钥匙pro-的转录 生长，抗分化基因。该建议的目标是测试该假设模型，如 以下具体目标。 目标1。确定BRD4-NUT MEGADOMAIN如何形成。 目的2。确定BRD4-NUT MEGADOMAIN的功能。 影响。预计成功完成目标将确定与BRD4-NUT相关的关键蛋白 病理性的巨域形成，并将确定新颖，可能更有效的治疗靶标 NMC和其他癌症。此外，我们预测BRD4-NUT MEGADOMAIN将提供一个模型 对癌症和发育中染色质构象的结构功能关系产生影响。