The role of homeostatic regulation between tumor suppressor DAB2IP and oncogenic Skp2 in prostate cancer growth

Yuh Shyan Tsai, Chen Li Lai, Chih Ho Lai, Kai Hsiung Chang, Kaijie Wu, Shu Fen Tseng, Ladan Fazli, Martin Gleave, Guanghua Xiao, Leah Gandee, Nima Sharifi, Loredana Moro, Tzong Shin Tzai, Jer Tsong Hsieh

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)6425-6436
Number of pages12
JournalOncotarget
Volume5
Issue number15
DOIs
Publication statusPublished - 2014

All Science Journal Classification (ASJC) codes

  • Oncology

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