Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development.
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.
Halkidou
Kalipso
K
1Prostate Research Group, School of Surgical and Reproductive Sciences, University of Newcastle, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Gnanapragasam
Vincent J
VJ
Mehta
Piyush B
PB
Logan
Ian R
IR
Brady
Mark E
ME
Cook
Susan
S
Leung
Hing Y
HY
Neal
David E
DE
Robson
Craig N
CN
D000123:Acetyltransferases / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D000728:Androgens / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology; D019556:COS Cells / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D051548:Histone Acetyltransferases; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D008297:Male; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D015854:Up-Regulation
D000728:Androgens; D000906:Antibodies; D011944:Receptors, Androgen; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5