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The role of DAB2IP in androgen receptor activation during prostate cancer progression

Oncogene volume 33, pages 1954–1963 (2014)Cite this article

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Abstract

Altered androgen-receptor (AR) expression and/or constitutively active AR are commonly associated with prostate cancer (PCa) progression. Targeting AR remains a focal point for designing new strategy of PCa therapy. Here, we have shown that DAB2IP, a novel tumor suppressor in PCa, can inhibit AR-mediated cell growth and gene activation in PCa cells via distinct mechanisms. DAB2IP inhibits the genomic pathway by preventing AR nuclear translocation or phosphorylation and suppresses the non-genomic pathway via its unique functional domain to inactivate c-Src. Also, DAB2IP is capable of suppressing AR activation in an androgen-independent manner. In addition, DAB2IP can inhibit several AR splice variants showing constitutive activity in PCa cells. In DAB2IP−/− mice, the prostate gland exhibits hyperplastic epithelia, in which AR becomes more active. Consistently, DAB2IP expression inversely correlates with AR activation status particularly in recurrent or metastatic PCa patients. Taken together, DAB2IP is a unique intrinsic AR modulator in normal cells, and likely can be further developed into a therapeutic agent for PCa.

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Acknowledgements

We thank Dr Jiang Min for editorial assistant and Rui Li for technical support. This work is supported in part by United States Army Grant W81XWH-04-1-0222 (JTH) and the National Natural Science Foundation of China (NSFC 81202014 to KW).

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Author notes

  1. K Wu and J Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    K Wu, C Gore & J-T Hsieh

  2. Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, China

    K Wu, Z Ning & D He

  3. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    J Liu, X Sun & O K Oz

  4. Department of Bioengineering, University of Texas at Arlington, Arlington, TX, USA

    S-F Tseng & G Alexandrakis

  5. Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    N Sharifi

  6. Vancouver Prostate Center, University of British Columbia, Vancouver, British Columbia, Canada

    L Fazli & M Gleave

  7. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    P Kapur

  8. Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA

    G Xiao

  9. Interdepartmental Program in Vascular Biology and Transplantation and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA

    W Min

  10. Department of Urology, China Medical University Hospital, Taichung, Taiwan

    C-R Yang & H-C Wu

  11. Graduate Institute of Cancer Biology, China Medical University Hospital, Taichung, Taiwan

    C-L Hsieh & J-T Hsieh

  12. Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan

    C-L Hsieh

  13. Department of Biotechnology, Asia University, Taichung, Taiwan

    C-L Hsieh

  14. School of Medicine, China Medical University, Taichung, Taiwan

    H-C Wu

  15. Department of General Surgery, Tongji Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China

    D Xie

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  1. K Wu
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Correspondence to D Xie or J-T Hsieh.

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Wu, K., Liu, J., Tseng, SF. et al. The role of DAB2IP in androgen receptor activation during prostate cancer progression. Oncogene 33, 1954–1963 (2014). https://doi.org/10.1038/onc.2013.143

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