title: The role of homeostatic regulation between tumor suppressor DAB2IP and oncogenic Skp2 in prostate cancer growth.
abstract: 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 suppressSkp2 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.
authors.affiliation: Department of Urology, Medical College and Hospital, National Cheng Kung University, Tainan, Taiwan; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Yuh-Shyan
authors.initials: YS
authors.lastname: Tsai
authors.affiliation: Department of Urology, Medical College and Hospital, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chen-Li
authors.initials: CL
authors.lastname: Lai
authors.affiliation: School of Medicine and Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Chih-Ho
authors.initials: CH
authors.lastname: Lai
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Kai-Hsiung
authors.initials: KH
authors.lastname: Chang
authors.affiliation: Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Kaijie
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Bioengineering, University of Texas at Arlington, Arlington, TX, USA.
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Tseng
authors.affiliation: VancouverProstate Center, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: VancouverProstate Center, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Guanghua
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Gandee
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Nima
authors.initials: N
authors.lastname: Sharifi
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Research Council (C.N.R.), Bari, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Moro
authors.affiliation: Department of Urology, Medical College and Hospital, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tzong-Shin
authors.initials: TS
authors.lastname: Tzai
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
authors.forename: Jer-Tsong
authors.initials: JT
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015870:Gene Expression; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C462952:DAB2IP protein, human; D044786:S-Phase Kinase-Associated Proteins; D020703:ras GTPase-Activating Proteins