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Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development
Kalipso Halkidou1, Vincent J Gnanapragasam, Piyush B Mehta
11Prostate Research Group, School of Surgical and Reproductive Sciences, University of Newcastle, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
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.
Insights
Tat interactive protein, 60 kDa (Tip60), an androgen receptor (AR) coactivator, accumulates in hormone-refractory prostate cancer. Androgen deprivation upregulates Tip60, suggesting its role in treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate cancer (CaP) initially responds to androgen deprivation therapy.
- Recurrence despite treatment suggests unknown molecular mechanisms driving progression.
- Androgen receptor (AR) coactivators are emerging as significant factors in CaP.
Purpose of the Study:
- To investigate the role of Tat interactive protein, 60 kDa (Tip60), an AR coactivator, in prostate cancer progression.
- To understand Tip60's involvement in the transition to androgen-independent CaP.
Main Methods:
- Analysis of Tip60 expression in hormone-refractory CaP biopsies and benign prostate hyperplasia.
- In vitro and in vivo studies using the LNCaP cell line and CWR22 xenograft model.
- Chromatin immunoprecipitation to assess Tip60 recruitment to the PSA gene promoter.
Main Results:
- Nuclear accumulation of Tip60 observed in hormone-refractory CaP, unlike benign or primary CaP.
- Androgen withdrawal increased Tip60 expression and nuclear localization in prostate cancer models.
- Androgen exposure decreased Tip60 expression and promoted cytoplasmic localization.
- Tip60 was recruited to the PSA gene promoter in both androgen-dependent and -independent CaP cells.
Conclusions:
- Tip60 expression and localization change with androgen status in prostate cancer.
- Tip60 may play a crucial role in the development of androgen-independent prostate cancer.
- These findings suggest Tip60 as a potential therapeutic target for advanced prostate cancer.