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1 DDX31 Regulates the P53-HDM2 Pathway and Rrna Gene

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1 DDX31 Regulates the P53-HDM2 Pathway and Rrna Gene Author Manuscript Published OnlineFirst on September 27, 2012; DOI: 10.1158/0008-5472.CAN-12-1645 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Fukawa T et al. DDX31 regulates the p53-HDM2 pathway and rRNA gene transcription through its interaction with NPM1 in renal cell carcinomas Tomoya Fukawa1,2, Masaya Ono3, Taisuke Matsuo1, Hisanori Uehara4, Tsuneharu Miki5, Yusuke Nakamura6, Hiro-omi Kanayama2, and Toyomasa 1 Katagiri Authors’ Affiliations: 1Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima; 2Department of Urology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima; 3Chemotherapy Division and Cancer Proteomics Project, National Cancer Center Research Institute, Tokyo; 4Molecular and Environmental Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima; 5Department of Urology, Kyoto Prefectural University of Medicine, Kyoto; 6Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo Japan. M. Ono and T. Matsuo are contributed equally to this work. Corresponding Author: Toyomasa Katagiri, Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, 3-18-15, 1 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2012 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 27, 2012; DOI: 10.1158/0008-5472.CAN-12-1645 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Fukawa T et al. Kuramoto-cho, Tokushima, 770-8503, Japan. Phone: 81-88-633-9477; Fax: 81-88-633-7986; E-mail: [email protected]. Running title DDX31 regulates the p53 activity in RCC cells. Keywords DDX31, renal cell carcinoma, NPM1, HDM2, p53 Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. Grant Support This work was supported by future advanced research project from The University of Tokushima (T. Katagiri). 2 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2012 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 27, 2012; DOI: 10.1158/0008-5472.CAN-12-1645 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Fukawa T et al. Abstract 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 RCC patients. 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 G1 phase cell cycle arrest and apoptosis. Taken together, our findings define a mechanism through which control of the DDX31NPM1 complex is likely to play critical roles in renal carcinogenesis. 3 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2012 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 27, 2012; DOI: 10.1158/0008-5472.CAN-12-1645 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Fukawa T et al. Introduction Renal cell carcinoma (RCC) is the most common cancer of the kidney (1, 2), and up to 30% of RCC patients present with metastatic disease (3, 4). At an early stage, RCC can be cured by surgical resection, which is the most effective treatment for localized RCC tumors (5). Moreover, cytokine therapies, such as interleukin-2 or interferon-, are widely used as a first-line treatment for metastatic disease. However, these treatments can be associated with severe toxicity (6-9). In addition to these anti-cancer drugs, several molecular target drugs, such as anti-VEGF antibody (Bevacizumab) and small molecule inhibitors (Sunitinib, Sorafenib, Axitinib, Temsirolimus and Everolimus) have been recommended as treatment options for metastatic RCC and have been shown to prolong survival (10-13). However, such treatments have also resulted in severe side effects (14-16). The prognostic factors that determine the treatment outcome in patients with metastatic RCC have been identified according to the patient’s status (17). These markers have been widely used to determine the best treatment approach and, as a result, may improve survival. At present there are no new relevant molecular markers that have been identified to predict the prognosis of RCC (18). Therefore, it is highly important to develop a new molecular target agent(s) against RCC as well as prognostic molecular markers. 4 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2012 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 27, 2012; DOI: 10.1158/0008-5472.CAN-12-1645 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Fukawa T et al. The “omics” technologies, including transcriptomics, genomics and proteomics, provide a detailed characterization of individual cancers that should help improve clinical strategies for neoplastic diseases through the development of novel drugs as well as providing the basis for personalized treatment (19). Hence, these technologies have helped identify diagnostic and therapeutic targets for cancer and understand the detailed molecular mechanism of carcinogenesis. To this end, we analyzed the expression profiling of clear cell RCC (ccRCC), which is a major histological type of RCC (the Gene Expression Omnibus database (GEO) accession number: GSE39364) (20), and identified and characterized DEAD (Asp-Glu-Ala-Asp) box polypeptide 31 (DDX31), a novel member of the DEAD box protein family. DDX31 is the human homologue of Saccharomyces cerevisiae DEAD box protein 7 (Dbp7), which was originally identified in a BLAST search of the Saccharomyces cerevesiae Genome Database (Stanford) as a new ATP-dependent RNA helicase (21). Dbp7 has been shown to play an important role in the assembly of pre-ribosomal particles during the biogenesis of the 60S ribosomal subunit (21). However, to date, no reports have characterized the biological function of DDX31, the human homologue 5 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2012 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 27, 2012; DOI: 10.1158/0008-5472.CAN-12-1645 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Fukawa T et al. of Dbp7, and the significance of its transactivation in clinical RCC progression. Here, we identify and characterize DDX31 as a clinical prognostic factor and a potential therapeutic target, and provide evidence that DDX31 is involved in regulating ribosomal RNA (rRNA) gene transcription and the p53−HDM2 pathway in renal carcinogenesis. Materials and Methods Cell lines and specimens ACHN, Caki-1, Caki-2, 769-P, HK-2, HEK293 and COS-7 cells were obtained from the American Type Culture Collection (ATCC) between 1994-2012. OS-RC-2 was provided by the RIKEN BioResource Center (Tsukuba, Japan) in 2005. KC-12, KMRC-1, KMRC-20, and YCR-1 cells were kindly provided by Dr. Taro Shuin, Department of Urology, Kochi Medical School in 2006. All cells were cultured under conditions recommended by their respective depositors. We monitored the cell morphology of these cell lines by microscopy, and confirmed that they had maintained their morphological states by comparison with the original morphological images. No mycoplasma contamination was detected in cultures of all of these cell lines using a Mycoplasma Detection Kit (Roche) in 2011. Surgically-resected 6 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2012 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 27, 2012; DOI: 10.1158/0008-5472.CAN-12-1645 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Fukawa T et al. RCC tissue samples and their corresponding clinical information were acquired from The University of Tokushima Hospital after obtaining written informed consent. This study, as well as the use of all clinical materials described above, was approved by the Ethical Committee of The University of Tokushima. Plasmids Plasmids used in this study are described in Supplementary Materials and Methods. Quantitative and semi-quantitative reverse transcription-PCR The extraction of total RNA from cultured cells and RCC clinical tissues, reverse transcription, and subsequent PCR-amplification were performed as previously described (1). -actin was used as a quantitative control. The sequences of each primer set are described in Supplementary Table S1. Generation
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