Role of SETD5 in Chromatin Regulation and Tumorigenesis

摘要 我们的首要目标是更好地理解细胞翻译后修饰(PTM)的作用 癌症中的蛋白质，其基本假设是催化添加或移除 这些PTM是癌症的候选治疗靶点。而像蛋白激酶这样的酶已经 在癌症中被广泛研究的新类别的酶最近已成为潜在的癌症靶点。在……里面 特别是，人类蛋白质组中预计存在100多个赖氨酸甲基转移酶(Kmt)。 其中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专一性 这些酶仍然是未知的。这里要检验的一个中心假设是，揭示 孤儿KMT可能在蛋白质赖氨酸甲基化信号和癌症生物学之间提供新的联系。 在这里，我们关注候选的KMT SETD5(设置结构域蛋白5)作为潜在的关键调节因子 肿瘤发生学。SETD5突变与智力残疾和自闭症的病因学有关 精神错乱。SETD5也与影响含有KRAS激活突变的肿瘤有关 癌基因，如胰腺癌。然而，SETD5是一种孤立的酶和任何潜在的知识 内源性底物和这种候选酶在细胞和体内的整体作用方式尚不清楚。 根据初步观察，我们假设SETD5通过对染色质动力学的调节， 管理对正常细胞行为重要的表观遗传程序，并促进肿瘤的发生。 目标1的目的是阐明SETD5的生理催化活性和SETD5的分子功能 染色质上的SETD5。我们还将研究SETD5的交互伙伴和针对SETD5的机制 对基因组的影响。在目标2中，我们研究了SETD5在致癌RAS途径驱动的肿瘤中的作用。我们 将检验SETD5与RAS信号合作促进细胞无限扩张的假设 用小鼠胰腺导管腺癌和肺腺癌两种肿瘤模型体内癌细胞 大多数致命的人类癌症中，KRAS经常被激活。我们还将研究肿瘤的致癌作用 人胰腺癌和肺癌患者移植瘤组织中SETD5的表达及意义 SETD5作为潜在的治疗靶点。最后，我们重点研究了SETD5在细胞内癌症中的作用模式 在活体内。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SETD5作为治疗致命癌症的相关和可用药物靶点。

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.