ABSTRACT
The androgen receptor (AR) has a central role in prostate cancer progression, particularly treatment-resistance disease including castration-resistant prostate cancer. Loss of the p53 tumor suppressor, a nuclear transcription factor, is also known to contribute to prostate malignancy. Here we report that p53 is translocated to the cytoplasm by androgen-mediated induction of G3BP2, a newly described direct target gene of AR. G3BP2 induces both cell cycle progression and blocks apoptosis. Translocation of p53 is regulated by androgen-dependent sumoylation mediated by the G3BP2-interacting SUMO-E3 ligase, RanBP2. G3BP2 knockdown results in reduced tumor growth and increased nuclear p53 accumulation in mouse xenograft models of prostate cancer with or without long-term androgen deprivation. Moreover, strong cytoplasmic p53 localization is correlated clinically with elevated G3BP2 expression and predicts poor prognosis and disease progression to the hormone-refractory state. Our findings reveal a new AR-mediated mechanism of p53 inhibition that promotes treatment-resistant prostate cancer.
Subject(s)
Androgens/metabolism , Carrier Proteins/metabolism , Molecular Chaperones/metabolism , Nuclear Pore Complex Proteins/metabolism , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms/metabolism , Tumor Suppressor Protein p53/metabolism , Active Transport, Cell Nucleus , Adaptor Proteins, Signal Transducing , Androgens/deficiency , Animals , Carrier Proteins/biosynthesis , Cell Line, Tumor , Disease Progression , Heterografts , Humans , Male , Mice , Prostatic Neoplasms/pathology , Prostatic Neoplasms, Castration-Resistant/pathology , RNA-Binding Proteins , Receptors, Androgen/metabolism , Sumoylation , TransfectionABSTRACT
Androgen receptor (AR) functions as a ligand-dependent transcription factor to regulate its downstream signaling for prostate cancer progression. AR complex formation by multiple transcription factors is important for enhancer activity and transcriptional regulation. However, the significance of such collaborative transcription factors has not been fully understood. In this study, we show that Oct1, an AR collaborative factor, coordinates genome-wide AR signaling for prostate cancer growth. Using global analysis by chromatin immunoprecipitation sequencing (ChIP-seq), we found that Oct1 is recruited to AR-binding enhancer/promoter regions and facilitates androgen signaling. Moreover, a major target of AR/Oct1 complex, acyl-CoA synthetase 3 (ACSL3), contributes to tumor growth in nude mice, and its high expression is associated with poor prognosis in prostate cancer patients. Next, we examined the therapeutic effects of pyrrole-imidazole polyamides that target the Oct1-binding sequence identified in the center of the ACSL3 AR-binding site. We observed that treatment with Oct1 polyamide severely blocked the Oct1 binding at the ACSL3 enhancer responsible for its transcriptional activity and ACSL3 induction. In addition, Oct1 polyamides suppressed castration-resistant tumor growth and specifically repressed global Oct1 chromatin association and androgen signaling in prostate cancer cells, with few nonspecific effects on basal promoter activity. Thus, targeting Oct1 binding could be a novel therapeutic strategy for AR-activated castration-resistant prostate cancer.
Subject(s)
Androgen Receptor Antagonists/pharmacology , Nylons/pharmacology , Octamer Transcription Factor-1/genetics , Prostatic Neoplasms, Castration-Resistant/genetics , Receptors, Androgen/metabolism , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Coenzyme A Ligases/genetics , Coenzyme A Ligases/metabolism , Genomics , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Male , Mice , Mice, Nude , Molecular Targeted Therapy , Nylons/chemistry , Octamer Transcription Factor-1/metabolism , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Pyrroles/chemistry , Pyrroles/pharmacology , Receptors, Androgen/genetics , Signal Transduction , TransfectionABSTRACT
We evaluated clinical efficacies of transvaginal mesh (TVM) reconstruction alone and those concomitant with a TVT/TOT sling for the treatment of pelvic organ prolapse (POP) and stress urinary incontinence (SUI). Between January 2006 and February 2007, 138 female patients with POP underwent TVM reconstruction. The mean age was 66.6 years (range: 52-84). Fourteen individuals were qualified as grade II in the POP quantification (POP-Q) system, 85 and 39 were grades III and IV, respectively. One hundred and seventeen of 138 (85 %) cases showed SUI. Twenty-one patients without SUI underwent TVM alone, and 117 cases with SUI underwent TVM concomitant with TVT/TOT sling. Mean operation time and intra-operative bleeding was 79 min (range: 25-177) and 74 ml (range: 10-429), respectively. Mean follow-up period is 5.3 months (range: 1-14). The vaginal prolapses were cured (grade 0) in 129 cases (93 %) after the surgery. Total inter-national prostate symptom score (IPSS), its QOL score, International Consultation on Incontinence Questionnaires Short Form (ICIQ-SF) significantly improved (from 12.6 to 3.9; p < 0.0001, from 5.0 to 1.0; p < 0.0001, and from 6.1 to 2.5; p < 0.01, respectively). Six of 21 cases (29%) who underwent TVM alone showed postoperative de-novo SUI. In contrast, 116 cases (99%) who underwent TVM concomitant with TVT/TOT, experienced a cure of SUI. Maximum flow rate did not change postoperatively in the both groups. In conclusion, the short-term efficacies of TVM reconstruction for POP are excellent, and a concomitant TVT/TOT sling prevents postoperative SUI.
