DDX31 Regulates the p53-HDM2 Pathway and rRNA Gene Transcription through Its Interaction with NPM1 in Renal Cell Carcinomas

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-11, Vol.72 (22), p.5867-5877
• Main Authors: FUKAWA, Tomoya, ONO, Masaya, MATSUO, Taisuke, UEHARA, Hisanori, MIKI, Tsuneharu, NAKAMURA, Yusuke, KANAYAMA, Hiro-Omi, KATAGIRI, Toyomasa
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Cell Nucleolus - genetics; Cell Nucleolus - metabolism; COS Cells; DEAD-box RNA Helicases - biosynthesis; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; HEK293 Cells; Humans; Immunohistochemistry; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidneys; Medical sciences; Nephrology. Urinary tract diseases; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pharmacology. Drug treatments; Prognosis; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; RNA, Ribosomal - genetics; Signal Transduction; Transcription, Genetic; Transfection; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Tumors of the urinary system; Up-Regulation
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-1645

Studies of renal cell carcinoma (RCC) have led to the development of new molecular-targeted drugs but its oncogenic origins remain poorly understood. Here, we report the identification and critical roles in renal carcinogenesis for DDX31, a novel nucleolar protein upregulated in the vast majority of human RCC. Immunohistochemical overexpression of DDX31 was an independent prognostic factor for patients with RCC. RNA interference (RNAi)-mediated attenuation of DDX31 in RCC cells significantly suppressed outgrowth, whereas ectopic DDX31 overexpression in human 293 kidney cells drove their proliferation. Endogenous DDX31 interacted and colocalized with nucleophosmin (NPM1) in the nucleoli of RCC cells, and attenuation of DDX31 or NPM1 expression decreased pre-ribosomal RNA biogenesis. Notably, in DDX31-attenuated cells, NPM1 was translocated from nucleoli to the nucleoplasm or cytoplasm where it bound to HDM2. As a result, HDM2 binding to p53 was reduced, causing p53 stablization with concomitant G(1) phase cell-cycle arrest and apoptosis. Taken together, our findings define a mechanism through which control of the DDX31-NPM1 complex is likely to play critical roles in renal carcinogenesis.