Ubc9 as a novel target for cancer therapy

描述(由申请人提供)： SUMO(小泛素相关修饰物)偶联或SUMO参与调节转录因子的活性，介导蛋白质核移位或亚核结构的形成，以及蛋白质的稳定性，从而调节一些关键的细胞活动。由于Ubc9是唯一的E2结合酶，在这些方面都是必需的，因此人们认为Ubc9在这些方面发挥着核心作用，它通过调节SUMO，最终影响细胞的生长和癌症的发展。我们的初步研究表明，Ubc9的表达变化与人类的恶性肿瘤有关。此外，对小鼠异种移植模型的实验表明，Ubc9在肿瘤发生中发挥了作用。我们的长期目标是更好地了解Ubc9介导的肿瘤发生的基础，并开发基于Ubc9的癌症治疗药物。具体目的是：1)通过短的双链干扰RNA(SiRNA)和可能阻断Ubc9与相扑相互作用的小化合物来靶向Ubc9。这些实验将使我们不仅能够进一步证明Ubc9在肿瘤发生中的作用，而且还能够识别潜在的治疗药物。2)检测Ubc9-siRNA在小鼠异种移植模型中的治疗作用。因此，合成的Ubc9-siRNA或基于载体的Ubc9-siRNA将被输送到荷瘤动物体内，以确定其对肿瘤生长的影响。3)分析Ubc9介导的肿瘤发生的分子机制。来自过度表达野生型Ubc9或显性阴性Ubc9或Ubc9-siRNA的细胞的肿瘤将通过微阵列技术用于基因谱分析以识别基因 或与Ubc9.4相关的通路)分析Ubc9调控。我们的初步研究表明，紫外线照射是一种众所周知的肿瘤促进剂，可以诱导Ubc9的表达，这表明Ubc9在紫外线诱导的致癌过程中发挥了作用。因此，我们将对Ubc9的调控机制进行实验研究，包括Ubc9启动子的活性、Ubc9 mRNA和蛋白的稳定性以及影响其表达的表观遗传因素。总之，建议的工作将提供关于Ubc9作为新的治疗靶点的有用信息，以及对Ubc9介导的肿瘤发生的分子机制的新见解。因此，我们将能够开发出有价值的基于Ubc9的抗癌药物

DESCRIPTION (provided by applicant): SUMO (small ubiquitin-related modifier) conjugation or sumoylation has been implicated in regulating activity of transcription factors, mediating nuclear translocation of proteins or formation of subnuclear structures, and protein stability, thus modulating several critical cellular activities. Because Ubc9 is a sole E2 conjugating enzyme essential for sumoylation, it is believed to play a central role in these aspects through regulation of sumoylation, ultimately impacting cell growth and cancer development. Our preliminary studies have revealed that altered expression of Ubc9 is associated with human malignancy. Furthermore, experiments with the mouse xenograft model have suggested that Ubc9 plays a role in tumorigenesis. Our long-term objectives are to better understand the basis for Ubc9-mediated tumorigenesis and to develop Ubc9-based therapeutic agents for cancer treatment. Specific aims are to: 1) Target Ubc9 by a short double-stranded interfering RNA (siRNA) and by small chemical compounds that potentially block the interaction of Ubc9 with SUMO. These experiments will enable us not only to further demonstrate the role for Ubc9 in tumorigenesis, but also identify potential therapeutic agents. 2) Determine the therapeutic functions of Ubc9-siRNA in the mouse xenograft model. Thus, the synthetic Ubc9-siRNA or the vector-based Ubc9-siRNA will be delivered into tumor-bearing animals to determine their effect on the tumor growth. 3) Dissect molecular mechanisms of Ubc9-mediated tumorigenesis. Tumors derived from the cells overexpressing wild type Ubc9 or dominant negative Ubc9 or Ubc9-siRNA will be used for gene profiling by the microarray technology to identify genes or pathways associated with Ubc9.4) Analyze Ubc9 regulation. Our preliminary studies have indicated that UV irradiation, a well-known tumor promoter, induces Ubc9 expression, suggesting a role for Ubc9 in UV-induced carcinogenesis. Thus, experiments will be carried out to investigate the underlying mechanism of Ubc9 regulation, including Ubc9 promoter activity, stability of Ubc9 mRNA and protein, and epigenetic factors that affect its expression. Together, the proposed work will provide useful information on Ubc9 as a novel therapeutic target as well as new insight into the molecular mechanism of Ubc9-mediated tumorigenesis. As a result, we will be able to develop valuable Ubc9-based anticancer agents