p68/DdX5 supports β-Catenin & RNAP II during androgen receptor mediated transcription in prostate cancer

The DEAD box RNA helicase p68 (Ddx5) is an important androgen receptor (AR) transcriptional co-activator in prostate cancer (PCa) and is over-expressed in late stage disease. β-Catenin is a multifunctional protein with important structural and signalling functions which is up-regulated in PCa and similar to p68, interacts with the AR to co-activate expression of AR target genes. Importantly, p68 forms complexes with nuclear β-Catenin and promotes gene transcription in colon cancer indicating a functional interplay between these two proteins in cancer progression. In this study, we explore the relationship of p68 and β-Catenin in PCa to assess their potential co-operation in AR-dependent gene expression, which may be of importance in the development of castrate resistant prostate cancer (CRPCa). We use immunoprecipitation to demonstrate a novel interaction between p68 and β-Catenin in the nucleus of PCa cells, which is androgen dependent in LNCaP cells but androgen independent in a hormone refractory derivative of the same cell line (representative of the CRPCa disease type). Enhanced AR activity is seen in androgen-dependent luciferase reporter assays upon transient co-transfection of p68 and β-Catenin as an additive effect, and p68-depleted Chromatin-Immunoprecipitation (ChIP) showed a decrease in the recruitment of the AR and β-Catenin to androgen responsive promoter regions. In addition, we found p68 immunoprecipitated with the processive and non-processive form of RNA polymerase II (RNAP II) and show p68 recruited to elongating regions of the AR mediated PSA gene, suggesting a role for p68 in facilitating RNAP II transcription of AR mediated genes. These results suggest p68 is important in facilitating β-Catenin and AR transcriptional activity in PCa cells

Epigenetic regulation of prostate cancer

Prostate cancer is a commonly diagnosed cancer in men and a leading cause of cancer deaths. Whilst the underlying mechanisms leading to prostate cancer are still to be determined, it is evident that both genetic and epigenetic changes contribute to the development and progression of this disease. Epigenetic changes involving DNA hypo- and hypermethylation, altered histone modifications and more recently changes in microRNA expression have been detected at a range of genes associated with prostate cancer. Furthermore, there is evidence that particular epigenetic changes are associated with different stages of the disease. Whilst early detection can lead to effective treatment, and androgen deprivation therapy has a high response rate, many tumours develop towards hormone-refractory prostate cancer, for which there is no successful treatment. Reliable markers for early detection and more effective treatment strategies are, therefore, needed. Consequently, there is a considerable interest in the potential of epigenetic changes as markers or targets for therapy in prostate cancer. Epigenetic modifiers that demethylate DNA and inhibit histone deacetylases have recently been explored to reactivate silenced gene expression in cancer. However, further understanding of the mechanisms and the effects of chromatin modulation in prostate cancer are required. In this review, we examine the current literature on epigenetic changes associated with prostate cancer and discuss the potential use of epigenetic modifiers for treatment of this disease

High incidence of venous thromboembolic events in lung transplant recipients.

BACKGROUND: Previous studies have reported a 12% incidence of venous thromboembolic events (VTEs) in lung transplant recipients (LTRs). Characterization of risk factors for VTEs in LTRs is lacking. We identified the incidence and risk factors associated with post-transplant VTEs. METHODS: A retrospective review of 153 LTRs from 1994 to 2006 was performed. Patients were categorized by age, race, gender, weight, underlying diagnosis, procedure, ischemic time, length of stay (LOS), cardiopulmonary bypass (CPB), location and number of VTEs, mobility, immunosuppression, renal, hepatic, hematologic and coagulation profiles and nutritional status. RESULTS: A single VTE occurred in 29% of LTRs within the study period. Fifty-eight percent had multiple VTEs and 7% had a radiologically confirmed pulmonary embolism. Median time from transplant to first VTE was 69 days. Sixty percent of VTEs occurred within 1 year, 20% of which occurred within the first month, 19% between 2 and 5 years, and 13% at beyond 5 years post-transplant. Seventy-six percent of VTEs occurred during hospitalization, 19% during outpatient status. Forty-eight percent were of the upper extremity and 47% were of the lower extremity. Sixty-one percent of LTRs were taking cyclosporine and 39% tacrolimus. VTE and non-VTE groups were similar in age, weight, body mass index (BMI), ischemic time, procedure or underlying diagnosis precipitating the need for transplant. Univariate analysis revealed LOS and CPB as significant predictors of a single VTE (p = 0.036, hazard ratio [HR] 1.006 and p = 0.045, HR 1.91, respectively). Multivariate analysis revealed only CPB as a significant predictor (p = 0.047, HR 1.929). CONCLUSIONS: Analysis of a cohort of LTRs for a median period of 1.5 years revealed a VTE incidence much higher than previously reported, especially within the first month after transplantation