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.

摘要 我们的首要目标是更好地了解细胞的翻译后修饰（PTM）的作用， 癌症中的蛋白质与潜在的假设，催化添加或去除的酶， 这些PTM是癌症的候选治疗靶点。虽然酶如蛋白激酶已经被广泛应用于 在癌症中进行了广泛的研究，最近出现了作为潜在癌症靶点的新类型的酶。在 特别地，超过100种赖氨酸甲基转移酶（KMT）被预测存在于人类蛋白质组中 并且许多与癌症病因学有关。然而，许多化合物的催化活性和底物特异性不高， 这些酶仍然是未知的。这里要检验的一个中心假设是， 孤儿KMT可能提供蛋白质赖氨酸甲基化信号传导和癌症生物学之间的新联系。 在这里，我们集中在候选人KMT SETD5（SET结构域蛋白5）作为一个潜在的关键调节因子， 肿瘤发生SETD5突变与智力残疾和自闭症谱系的病因有关 紊乱SETD5还涉及影响KRAS中携带激活突变的肿瘤 癌基因，如胰腺癌。然而，SETD5是一种孤儿酶， 内源性底物和这种候选酶在细胞和体内的总体作用模式是模糊的。 基于初步观察，我们假设SETD 5通过调节染色质动力学， 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。 目的1是阐明SETD 5的生理催化活性和SETD 5的分子功能。 染色质处的SETD5。我们还将研究SETD 5相互作用的伙伴和机制，针对SETD 5 到基因组。在目的2中，我们表征了SETD 5在由致癌RAS途径驱动的肿瘤中的作用。我们 我们将测试SETD5与RAS信号传导合作促进细胞无限扩张的假设。 使用胰腺导管腺癌和肺腺癌的小鼠模型， 大多数致命的人类癌症，其中KRAS经常被激活。我们还将研究肿瘤的作用 使用患者来源的异种移植胰腺癌和肺癌模型， SETD 5作为潜在的治疗靶点。最后，我们关注的是SETD 5在细胞癌症中的作用模式 和体内。我们将使用尖端的基因传递技术在体内对胰腺癌进行基因修饰。 一个长期目标是评估SETD 5作为治疗致命癌症的相关和药物靶点。