The role of homeostatic regulation between tumor suppressor DAB2IP and oncogenic Skp2 in prostate cancer growth
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Yuh-Shyan Tsai1,2, Chen-Li Lai1, Chih-Ho Lai3, Kai-Hsiung Chang4, Kaijie Wu5, Shu-Fen Tseng6, Ladan Fazli7, Martin Gleave7, Guanghua Xiao8, Leah Gandee2, Nima Sharifi4, Loredana Moro9, Tzong-Shin Tzai1 and Jer-Tsong Hsieh2,10
1 Department of Urology, Medical College and Hospital, National Cheng Kung University, Tainan, Taiwan
2 Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
3 School of Medicine and Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
4 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
5 Department of Urology, The First Affiliated Hospital, Medical School of Xi’an Jiaotong University, Xi’an, China
6 Department of Bioengineering, University of Texas at Arlington, Arlington, TX, USA
7 Vancouver Prostate Center, University of British Columbia, Vancouver, British Columbia, Canada
8 Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
9 Institute of Biomembranes and Bioenergetics, National Research Council (C.N.R.), Bari, Italy
10 Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan
Jer-Tsong Hsieh, email:
Tzong-Shin Tzai, email:
Keywords: prostate neoplasm, Skp2, DAB2IP, ubiquitin
Received: May 29, 2014 Accepted: July 16, 2014 Published: July 17, 2014
Altered DAB2IP gene expression often detected in prostate cancer (PCa) is due to epigenetic silencing. In this study, we unveil a new mechanism leading to the loss of DAB2IP protein; an oncogenic S-phase kinase-associated protein-2 (Skp2) as E3 ubiquitin ligase plays a key regulator in DAB2IP degradation. In order to unveil the role of Skp2 in the turnover of DAB2IP protein, both prostate cell lines and prostate cancer specimens with a variety of molecular and cell biologic techniques were employed. We demonstrated that DAB2IP is regulated by Skp2-mediated proteasome degradation in the prostate cell lines. Further analyses identified the N-terminal DAB2IP containing the ubiquitination site. Immunohistochemical study exhibited an inverse correlation between DAB2IP and Skp2 protein expression in the prostate cancer tissue microarray. In contrast, DAB2IP can suppress Skp2 protein expression is mediated through Akt signaling. The reciprocal regulation between DAB2IP and Skp2 can impact on the growth of PCa cells. This reciprocal regulation between DAB2IP and Skp2 protein represents a unique homeostatic balance between tumor suppressor and oncoprotein in normal prostate epithelia, which is apparently altered in cancer cells. The outcome of this study has identified new potential targets for developing new therapeutic strategy for PCa.
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