Abstract 765: DDX31 regulates p53 tumor suppressive activity in renal cell carcinomas.

Abstract Renal cell carcinoma (RCC) is the most common cancer of the kidney, and up to 30% of patients with RCC present with metastatic disease, yet its oncogenic origins are poorly understood. At an early stage, RCC can be cured by surgical resection, which is the most effective treatment for localized RCC tumors .Moreover, cytokine therapies, such as interleukin-2 or IFN-a, are widely used as a first-line treatment for metastatic disease. Therefore, it is highly important to develop a new molecular target agent(s) against RCC. However, these treatments can be associated with severe toxicity. Therefore, it is highly important to develop a new molecular target agent(s) against RCC. To identify therapeutic targets for cancer and understand the detailed molecular mechanism of carcinogenesis, we analyzed the expression profiling of clear cell RCC (ccRCC), which is a major histologic type of RCC, and identified DEAD (Asp-Glu-Ala-Asp) box polypeptide 31 (DDX31), a novel member of the DEAD box protein family, which is frequently up-regulated in the vast majority of human RCCs. Immunohistochemistry analysis indicated that DDX31 positivity was an independent prognostic factor for RCC patients. RNAi-mediated knockdown of DDX31 significantly suppressed RCC cell growth. Concordantly, expressing exogenous DDX31 promoted the growth of HEK293 cells. We also found that endogenous DDX31 interacted and colocalized with nucleophosmin (NPM1), involved in ribosome biogenesis and regulation of p53–HDM2 pathway, in nucleoli. Knockdown of DDX31 or NPM1 decreased pre-ribosome RNA biogenesis. Interestingly, in DDX31-knockdown cells, NPM1 was translocated from nucleoli to the nucleoplasm or cytoplasm, and then bound to HDM2, which prevented HDM2 from interacting with the p53 protein, resulting in p53 stabilization by inhibiting p53 ubiquitination. Our findings suggest that the DDX31–NPM1 complex plays critical roles in cell proliferation of RCC. Citation Format: Toyomasa Katagiri, Tomoya Fukawa, Taisuke Matsuo, Hiro-omi Kanayama. DDX31 regulates p53 tumor suppressive activity in renal cell carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 765. doi:10.1158/1538-7445.AM2013-765