[Abstract unavailable

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.

The androgen receptor (AR) is a member of the nuclear steroid hormone receptor family and is thought to play an important role in the development of both androgendependent and androgen-independent prostatic malignancy. Elucidating roles by which cofactors regulate AR transcriptional activity may provide therapeutic advancement for prostate cancer (PCa). The DEAD box RNA helicase p68 (Ddx5) was identified as a novel AR-interacting protein by yeast two-hybrid screening, and we sought to examine the involvement of p68 in AR signaling and PCa. The p68-AR interaction was verified by colocalization of overexpressed protein by immunofluorescence and confirmed in vivo by coimmunoprecipitation in the PCa LNCaP cell line. Chromatin immunoprecipitation in the same cell line showed AR and p68 recruitment to the promoter region of the androgenresponsive prostate-specific antigen (PSA) gene. Luciferase reporter, minigene splicing assays, and RNA interference (RNAi) were used to examine a functional role of p68 in ARregulated gene expression, whereby p68 targeted RNAi reduced AR-regulated PSA expression, and p68 enhanced AR-regulated repression of CD44 splicing (P = 0.008). Tyrosine phosphorylation of p68 was found to enhance coactivation of ligand-dependent transcription of AR-regulated luciferase reporters independent of ATP-binding. Finally, we observe increased frequency and expression of p68 in PCa compared with benign tissue using a comprehensive prostate tissue microarray (P = 0.003; P = 0.008). These findings implicate p68 as a novel AR transcriptional coactivator that is significantly overexpressed in PCa with a possible role in progression to hormone-refractory disease.

The novel mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ ERK5) pathway has been implicated in the regulation of cellular proliferation. MEK5 expression has been detected in prostate cancer cells, although the significance of the MEK5/ERK5 pathway in human prostate cancer has not been tested. We examined MEK5 expression in 127 cases of prostate cancer and 20 cases of benign prostatic hypertrophy (BPH) by immunohistochemistry and compared the results to clinical parameters. We demonstrated that MEK5 expression is increased in prostate cancer as compared to benign prostatic tissue. Strong MEK5 expression correlates with the presence of bony metastases and less favourable disease-specific survival. Furthermore, among the patients with high Gleason score of 8-10, MEK5 overexpression has an additional prognostic value in survival. MEK5 transfection experiments confirm its ability to induce proliferation (Po0.0001), motility (P ¼ 0.0001) and invasion in prostate cancer cells (P ¼ 0.0001). MEK5 expression drastically increased MMP-9, but not MMP-2 mRNA expression. Luciferase report assays suggest that the À670/MMP-9 promoter is upregulated by MEK5 and electromobility shift assay further suggests the involvement of activator protein-I (AP-1), but not the NF-jB, binding site in the MMP-9 promoter. Using an AP-1 luciferase construct, activation of MEK5 was confirmed to enhance AP-1 activities up to twofold. Taken together, our results establish MEK5 as a key signalling molecule associated with prostate carcinogenesis. As the MEK5/ERK5 interaction is highly specific, it represents a potential target of therapy.