OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo

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• 作者：Diego Iglesias-Gato (1)
  Yin-Choy Chuan (1)
  Ning Jiang (1) (2)
  Charlotte Svensson (1)
  Jing Bao (1) (2)
  Indranil Paul (1)
  Lars Egevad (3)
  Benedikt M Kessler (4)
  Pernilla Wikstr枚m (5)
  Yuanjie Niu (2)
  Amilcar Flores-Morales (1)
  
  1. The Novo Nordisk Foundation Center for Protein Research ; Faculty of Health Sciences ; University of Copenhagen ; 2200 ; Copenhagen ; Denmark
  2. Tianjin Institute of Urology ; Tianjin Medical University ; 300211 ; Tianjin ; China
  3. Section of Urology ; Department of Surgical Science Karolinska Institutet ; 17176 ; Stockholm ; Sweden
  4. Target Discovery Institute ; Nuffield Department of Clinical Medicine ; University of Oxford ; OX3 7BN ; Oxford ; UK
  5. Department of Medical Biosciences ; Pathology ; Ume氓 University ; 90185 ; Ume氓 ; Sweden
  
• 关键词：Otubain 1 ; Deubiquitinase ; Ubiquitin ; Prostate cancer ; RhoA ; Androgen
• 刊名：Molecular Cancer
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：14
• 期：1
• 全文大小：2,912 KB
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• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

Background Ubiquitination is a highly dynamic and reversible process with a central role in cell homeostasis. Deregulation of several deubiquitinating enzymes has been linked to tumor development but their specific role in prostate cancer progression remains unexplored. Methods RNAi screening was used to investigate the role of the ovarian tumor proteases (OTU) family of deubiquitinating enzymes on the proliferation and invasion capacity of prostate cancer cells. RhoA activity was measured in relation with OTUB1 effects on prostate cancer cell invasion. Tumor xenograft mouse model with stable OTUB1 knockdown was used to investigate OTUB1 influence in tumor growth. Results Our RNAi screening identified OTUB1 as an important regulator of prostate cancer cell invasion through the modulation of RhoA activation. The effect of OTUB1 on RhoA activation is important for androgen-induced repression of p53 expression in prostate cancer cells. In localized prostate cancer tumors OTUB1 was found overexpressed as compared to normal prostatic epithelial cells. Prostate cancer xenografts expressing reduced levels of OTUB1 exhibit reduced tumor growth and reduced metastatic dissemination in vivo. Conclusions OTUB1 mediates prostate cancer cell invasion through RhoA activation and promotes tumorigenesis in vivo. Our results suggest that drugs targeting the catalytic activity of OTUB1 could potentially be used as therapeutics for metastatic prostate cancer.