Ubc9 as a novel target for cancer therapy

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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