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Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development

Oncogene volume 22, pages 2466–2477 (2003)Cite this article

Abstract

Prostate cancer (CaP) is initially androgen sensitive and responsive to hormone ablation therapy. However, cancer growth recurs despite androgen deprivation in the majority of cases of advanced disease. The molecular basis of this progression still remains unknown. The significance of androgen receptor (AR) coactivator proteins in this androgen-dependent malignancy is only beginning to emerge. In the present study, we examined the role of Tat interactive protein, 60 kDa (Tip60), an AR coactivator, in CaP progression. In hormone refractory CaP biopsies, we observed a nuclear accumulation of Tip60 expression in contrast to a more diffuse distribution pattern observed in benign prostate hyperplasia and primary CaP. Furthermore, in both the prostate xenograft model CWR22 and the LNCaP CaP cell line, we observed that androgen withdrawal promoted upregulation of Tip60 as well as nuclear accumulation. In contrast, androgen exposure resulted in decreased Tip60 expression that was more closely linked to a cytoplasmic presence. Chromatin immunoprecipitation analysis revealed Tip60's recruitment to the PSA gene promoter in both androgen-dependent and -independent cell lines. Thus, in vitro and in vivo data support a possible role for Tip60 in the molecular pathway leading to the development of androgen-independent CaP following long-term androgen deprivation therapy.

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Abbreviations

AR:

androgen receptor

CaP:

prostate cancer

ChlP:

chromatin immunoprecipitation

CWR22:

Case Western Reserve prostate xenograft strain 22

RT–PCR:

reverse transcription polymerase chain reaction

HR:

hormone refractory

SDM:

steroid-depleted medium

FM:

full medium

CaS:

bicalutamide (Casodex)

TURP:

transurethral resection of the prostate

PSA:

prostate-specific antigen

Tip60:

Tat interactive protein 60 kDa

AI:

androgen independent

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Acknowledgements

We are grateful to Yoshihiro Nakatani for generously providing us with the Tip60 cDNA, and Trevor Booth (Electron Microscopy Unit, Newcastle Medical School) for helpful discussions and excellent technical assistance.

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Authors and Affiliations

  1. Prostate Research Group, School of Surgical and Reproductive Sciences, University of Newcastle, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

    Kalipso Halkidou, Vincent J Gnanapragasam, Piyush B Mehta, Ian R Logan, Mark E Brady, Susan Cook, Hing Y Leung, David E Neal & Craig N Robson

  2. Oncology Centre, Addenbrooke Hospital, University of Cambridge, Cambridge, CB2 2QQ, UK

    David E Neal

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  1. Kalipso Halkidou
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Correspondence to Craig N Robson.

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Halkidou, K., Gnanapragasam, V., Mehta, P. et al. Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development. Oncogene 22, 2466–2477 (2003). https://doi.org/10.1038/sj.onc.1206342

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