Role of SETD5 in Chromatin Regulation and Tumorigenesis

SETD5 在染色质调节和肿瘤发生中的作用

• 批准号: 10586057
• 负责人: Pawel K. Mazur
• 金额: $ 37.83万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10586057
• 关键词: Attenuated; Biochemical; CRISPR/Cas technology; Cancer Biology; Cancer Etiology; Cancer Model; Cancer cell line; Cells; Chromatin; Classification; Complex; Development; Drug resistance; Enzymes; Epigenetic Process; Etiology; Excision; Foundations; Gene Delivery; Genes; Genetic; Genetic Screening; Genome; Goals; Growth; Histones; Human; Intellectual functioning disability; KRAS2 gene; Knowledge; Laboratories; Link; Literature; Lung Adenocarcinoma; Lysine; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mammalian Cell; Methylation; Methyltransferase; Modeling; Modification; Molecular; Mus; Mutate; Mutation; Nuclear; Oncogenes; Oncogenic; Orphan; Pancreatic Ductal Adenocarcinoma; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Post-Translational Protein Processing; Proliferating; Protein Kinase; Proteins; Proteome; Proteomics; Regulation; Role; SET Domain; Signal Pathway; Signal Transduction; Substrate Specificity; Techniques; Tertiary Protein Structure; Testing; Therapeutic; Work; Xenograft Model; autism spectrum disorder; cancer cell; cell behavior; cell transformation; complement system; developmental disease; drug development; druggable target; epigenetic silencing; experimental study; genetic corepressor; genome editing; human cancer mouse model; human tissue; in vitro activity; in vivo; inhibitor; lung cancer cell; mouse model; multidisciplinary; mutant; novel therapeutic intervention; pancreatic PDX models; pancreatic cancer cells; pancreatic cancer model; pancreatic ductal adenocarcinoma model; patient derived xenograft model; programs; therapeutic candidate; therapeutic target; translational approach; tumor; tumorigenesis; tumorigenic

ABSTRACT Our overarching goal is to better understand the role of post-translational modifications (PTMs) of cellular proteins in cancer with the underlying assumption that the enzymes that catalyze the addition or the removal of these PTMs are candidate therapeutic targets in cancer. While enzymes such as protein kinases have been extensively studied in cancer, new classes of enzymes have recently emerged as potential cancer targets. In particular, more than 100 lysine methyltransferases (KMTs) are predicted to be present in the human proteome and many are implicated in cancer etiology. However, the catalytic activity and substrate specificity for many of these enzymes remains unknown. A central hypothesis to be tested here is that uncovering the function of orphan KMTs may provide new links between protein lysine methylation signaling and cancer biology. Here we focus on the candidate KMT SETD5 (SET domain protein 5) as a potential critical regulator of tumorigenesis. SETD5 mutations are involved in the etiology of intellectual disabilities and autism spectrum disorders. SETD5 has also been implicated in influencing tumors harboring activating mutations in the KRAS oncogene, such as pancreas cancer. However, SETD5 is an orphan enzyme and knowledge of any potential endogenous substrates and the overall mode of action of this candidate enzyme in cells and in vivo is obscure. Based on preliminary observations, we hypothesize that SETD5, via regulation of chromatin dynamics, governs epigenetic programs important for normal cellular behaviors and promotes tumorigenesis. The goal of Aim 1 is to elucidate the physiologic catalytic activity of SETD5 and molecular functions of SETD5 at chromatin. We also will investigate SETD5 interacting partners and mechanisms of targeting SETD5 to the genome. In Aim 2 we characterize the role of SETD5 in tumors driven by oncogenic RAS pathway. We will test the hypothesis that SETD5 cooperates with RAS signaling to promote the unlimited expansion of cancer cells in vivo using mouse models of Pancreas Ductal Adenocarcinoma and Lung Adenocarcinoma, two most lethal human cancers in which KRAS is frequently activated. We will also investigate the tumorigenic role of SETD5 in human tissue using patient-derived xenograft pancreatic and lung cancer models and explore SETD5 as a potential therapeutic target. Finally, we focus on the mode of action of SETD5 in cancer in cells and in vivo. We will use cutting-edge gene delivery techniques to genetically modify pancreatic cancer in vivo. A long-term goal is to evaluate SETD5 as a relevant and druggable target for the treatment of lethal cancers.

抽象的 我们的总体目标是更好地了解细胞翻译后修饰（PTM）的作用 癌症中的蛋白质具有基本假设，即催化添加或去除的酶 这些PTM是癌症的候选治疗靶标。而诸如蛋白激酶之类的酶已经 在癌症中进行了广泛的研究，新的酶最近已成为潜在的癌症靶标。在 特别是，预计100多种赖氨酸甲基转移酶（KMT）存在于人类蛋白质组中 许多人与癌症病因有关。但是，许多许多 这些酶仍然未知。这里要测试的中心假设是发现的功能 孤儿KMT可以在蛋白质赖氨酸甲基化信号传导与癌症生物学之间提供新的联系。 在这里，我们关注候选KMT SetD5（Set域蛋白5）作为潜在的关键调节剂 肿瘤发生。智力残疾和自闭症谱系的病因涉及SetD5突变 疾病。 SETD5还与影响KRAS中携带激活突变的肿瘤有关 癌基因，例如胰腺癌。但是，setd5是孤儿酶，并且了解任何潜力 内源性底物和该候选酶在细胞和体内的总体作用方式是晦涩的。 基于初步观察，我们通过调节染色质动力学来假设SETD5， 控制对正常细胞行为重要的表观遗传程序并促进肿瘤发生。 目标1的目的是阐明setD5的生理催化活性和分子功能 染色质的setD5。我们还将调查setD5交互伙伴和靶向setD5的机制 到基因组。在AIM 2中，我们表征了SETD5在由致癌Ras途径驱动的肿瘤中的作用。我们 将测试SETD5与RAS信号合作以促进无限扩展的假设 使用胰腺导管腺癌和肺腺癌的小鼠模型在体内癌细胞，两个 大多数致命的人类癌症经常被激活。我们还将调查肿瘤性作用 使用患者衍生的异种移植胰腺和肺癌模型在人体组织中的SetD5的of setD5 SETD5作为潜在的治疗靶点。最后，我们专注于细胞中癌症中setD5的作用方式 和体内。我们将使用尖端的基因递送技术在体内遗传修饰胰腺癌。 一个长期的目标是评估SETD5作为治疗致命癌的相关且可药的靶标。