Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer.

BACKGROUND: Histone deacetylase 1 (HDAC1) is a co-repressor involved in differentiation and proliferation control. It is upregulated in malignant compared to benign tissue, and targets a number of transcription factors including p53. METHODS: By immunohistochemistry, HDAC1 protein expression was investigated in human prostate specimens and the CWR22 mouse xenograft model. Flow cytometry and deconvolution immunofluorescence were also performed. RESULTS: HDAC1 was upregulated in pre-malignant and malignant lesions, with the highest increase in expression in hormone refractory (HR) cancer. Using the CWR22 xenograft model we showed androgen dependent regulation of HDAC1. HDAC1 overexpression led to a significant increase in proliferation and a shift towards the undifferentiated cytokeratin (CK) profile in a PC3M derivative clone constitutively expressing HDAC1. CONCLUSION: This study underlines the importance of HDAC1 in cell proliferation and the development of prostate cancer (CaP) and proposes a mechanism for HDAC1 nuclear recruitment. HDAC1 may constitute a crucial therapeutic target particularly in the most lethal phase of androgen independence.

Putative involvement of the histone acetyltransferase Tip60 in ribosomal gene transcription.

Tip60 is a histone acetyltransferase (HAT) implicated in a wide range of cellular functions, including mRNA synthesis and DNA repair. In the present report we propose a model based on which Tip60 is actively involved in ribosomal gene transcription through acetylation of UBF, a ribosomal specific transcription factor, as well as through its direct recruitment to the human ribosomal gene promoter, as shown by chromatin immunoprecipitation experiments. Electron microscopy studies revealed that Tip60 resides in sites of active rDNA transcription within the nucleolus, while it co-localizes with UBF as shown by confocal microscopy. In addition, in vivo transcription assays demonstrated that the nucleolar fraction of Tip60 localizes to sites of newly synthesized rRNA. Finally, functional assays established that Tip60 complexes with, and targets UBF for acetylation. The present study underlines the importance of acetylation in rDNA transcription and directly implicates Tip60 in the process of ribosomal gene transcription.

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.