Co-targeting BET, CBP, and p300 inhibits neuroendocrine signalling in androgen receptor-null prostate cancer.

There are diverse phenotypes of castration-resistant prostate cancer, including neuroendocrine disease, that vary in their sensitivity to drug treatment. The efficacy of BET and CBP/p300 inhibitors in prostate cancer is attributed, at least in part, to their ability to decrease androgen receptor (AR) signalling. However, the activity of BET and CBP/p300 inhibitors in prostate cancers that lack the AR is unclear. In this study, we showed that BRD4, CBP, and p300 were co-expressed in AR-positive and AR-null prostate cancer. A combined inhibitor of these three proteins, NEO2734, reduced the growth of both AR-positive and AR-null organoids, as measured by changes in viability, size, and composition. NEO2734 treatment caused consistent transcriptional downregulation of cell cycle pathways. In neuroendocrine models, NEO2734 treatment reduced ASCL1 levels and other neuroendocrine markers, and reduced tumour growth in vivo. Collectively, these results show that epigenome-targeted inhibitors cause decreased growth and phenotype-dependent disruption of lineage regulators in neuroendocrine prostate cancer, warranting further development of compounds with this activity in the clinic. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Identification of new octamer transcription factor 1-target genes upregulated in castration-resistant prostate cancer.

Octamer transcription factor 1 (OCT1) is an androgen receptor (AR)-interacting partner and regulates the expression of target genes in prostate cancer cells. However, the function of OCT1 in castration-resistant prostate cancer (CRPC) is not fully understood. In the present study, we used 22Rv1 cells as AR-positive CRPC model cells to analyze the role of OCT1 in CRPC. We showed that OCT1 knockdown suppressed cell proliferation and migration of 22Rv1 cells. Using microarray analysis, we identified four AR and OCT1-target genes, disks large-associated protein 5 (DLGAP5), kinesin family member 15 (KIF15), non-SMC condensin I complex subunit G (NCAPG), and NDC80 kinetochore complex component (NUF2) in 22Rv1 cells. We observed that knockdown of DLGAP5 and NUF2 suppresses growth and migration of 22Rv1 cells. Furthermore, immunohistochemical analysis showed that positive expression of DLGAP5 in prostate cancer specimens is related to poor cancer-specific survival rates of patients. Notably, enhanced expression of DLGAP5 was observed in CRPC tissues of patients. Thus, our findings suggest that these four genes regulated by the AR/OCT1 complex could have an important role in CRPC progression.

CLDN8, an androgen-regulated gene, promotes prostate cancer cell proliferation and migration.

The proliferation of prostate cancer cells is controlled by the androgen receptor (AR) signaling pathway. However, the function of AR target genes has not been fully elucidated. In previous studies, we have identified global AR binding sites and AR target genes in prostate cancer cells. Here, we focused on Claudin 8 (CLDN8), a protein constituting tight junctions in cell membranes. We found one AR binding site in the promoter region and two functional androgen-responsive elements in the sequence. Reporter assay revealed that transcriptional activation of the CLDN8 promoter by androgen is dependent on these androgen-responsive elements. Furthermore, CLDN8 mRNA is induced by androgen time-dependently and the induction is blocked by AR inhibitor, suggesting that AR is involved in the transcriptional activation. In addition, our functional analyses by overexpression and knockdown of CLDN8 mRNA indicate that CLDN8 promotes prostate cancer cell proliferation and migration. Claudin 8 was overexpressed in prostate cancer clinical samples compared to benign tissues. Furthermore, we found that CLDN8 regulates intracellular signal transduction and stabilizes the cytoskeleton. Taken together, these results indicate that CLDN8 functions as an AR downstream signal to facilitate the progression of prostate cancer. Claudin 8 may be a novel molecular target for prostate cancer therapy.

A novel prognostic factor TRIM44 promotes cell proliferation and migration, and inhibits apoptosis in testicular germ cell tumor.

Tripartite motif 44 (TRIM44) is one of the TRIM family proteins that are involved in ubiquitination and degradation of target proteins by modulating E3 ubiquitin ligases. TRIM44 overexpression has been observed in various cancers. However, its association with testicular germ cell tumor (TGCT) is unknown. We aimed to investigate the clinical significance of TRIM44 and its function in TGCT. High expression of TRIM44 was significantly associated with α feto-protein levels, clinical stage, nonseminomatous germ cell tumor (NSGCT), and cancer-specific survival (P = 0.0009, P = 0.0035, P = 0.0004, and P = 0.0140, respectively). Multivariate analysis showed that positive TRIM44 IR was an independent predictor of cancer-specific mortality (P = 0.046). Gain-of-function study revealed that overexpression of TRIM44 promoted cell proliferation and migration of NTERA2 and NEC8 cells. Knockdown of TRIM44 using siRNA promoted apoptosis and repressed cell proliferation and migration in these cells. Microarray analysis of NTERA2 cells revealed that tumor suppressor genes such as CADM1, CDK19, and PRKACB were upregulated in TRIM44-knockdown cells compared to control cells. In contrast, oncogenic genes including C3AR1, ST3GAL5, and NT5E were downregulated in those cells. These results suggest that high expression of TRIM44 is associated with poor prognosis and that TRIM44 plays significant role in cell proliferation, migration, and anti-apoptosis in TGCT.

[The latest research of the molecular biomarker in prostate cancer].

The incidence of prostate cancer is rapidly increasing in Japan. Currently, the biomarker of prostate cancer is widely used in clinical is serum PSA only. We need to develop novel molecular markers (biomarkers) that diagnose early prostate cancer so that we can treat appropriately. Recently, the whole genome sequencing analysis has advanced that has made finding of novel molecular markers easier. The best molecular markers identified using personalized genome information will be useful to select appropriate treatment. These therapeutic options for each patient will improve the survival rate. We give an outline about the latest molecular marker basic research with reference to the articles.

Pyrrole-imidazole polyamide targeted to break fusion sites in TMPRSS2 and ERG gene fusion represses prostate tumor growth.

Aberrant overexpression of ERG induced by the TMPRSS2-ERG gene fusion is likely involved in the development of prostate cancer. Synthetic pyrrole-imidazole (PI) polyamides recognize and attach to the minor groove of DNA with high affinity and specificity. In the present study, we designed a PI polyamide targeting TMPRSS2-ERG translocation breakpoints and assessed its effect on human prostate cancer cells. Our study identified that this PI polyamide repressed the cell and tumor growth of androgen-sensitive LNCaP prostate cancer cells. Targeting of these breakpoint sequences by PI polyamides could be a novel approach for the treatment of prostate cancer.

Lower urinary tract symptoms in female patients with pelvic organ prolapse: efficacy of pelvic floor reconstruction.

OBJECTIVE: To evaluate the impact of pelvic floor reconstruction on lower urinary tract symptoms in patients with pelvic organ prolapse. METHODS: We carried out a prospective study at a single institution. A total of 223 female patients who underwent tension-free vaginal mesh surgery for pelvic organ prolapse between January 2006 and February 2010 were enrolled and prospectively evaluated. A total of 171 cases with concurrent stress urinary incontinence (76% of all cases) underwent concomitant transobturator tape sling. For evaluation of lower urinary tract symptoms, parameters included International Prostate Symptom Score, its quality of life score, International Consultation on Incontinence Questionnaires Short Form, overactive bladder questionnaire, maximal flow rate and postvoid residual. These parameters were evaluated at baseline, and at 3, 6 and 12 months after the surgery. RESULTS: The severity of International Prostate Symptom Score total scores significantly correlated with preoperative pelvic organ prolapse quantification stages, overactive bladder questionnaire total scores and International Consultation on Incontinence Questionnaires Short Form scores. A total of 37% of stage 4 showed ≥20 International Prostate Symptom Score (severe cases). Postvoid residual significantly increased in stage 4 compared with stage 2. Tension-free vaginal mesh improved International Prostate Symptom Score, overactive bladder questionnaire and International Consultation on Incontinence Questionnaires Short Form significantly, and also achieved grade 0 pelvic organ prolapse quantification in 91% of all cases at 1 year after surgery. Postvoid residual values significantly improved and remained stable for 1 year. Worse overactive bladder questionnaire score was a significant predictive factor for poor postoperative International Prostate Symptom Score. CONCLUSION: The tension-free vaginal mesh plus transobturator tape procedure improves lower urinary tract symptoms in the majority of patients presenting pelvic organ prolapse.

Ectopic adrenal adenoma causing gross hematuria: Steroidogenic enzyme profiling and literature review.

INTRODUCTION: Aberrant cortical adrenal tissues are not generally identified in adults. Herein, we present a very rare case of an ectopic adrenal tumor located in the renal hilum that caused gross hematuria. CASE PRESENTATION: A 33-year-old man suddenly presented with asymptomatic gross hematuria. Abdominal computed tomography revealed a 35-mm mass in the left renal hilum encroaching the renal vein. Following the surgical removal with frozen section of the mass, his gross hematuria immediately improved. Pathological analysis of the specimen revealed the features adrenal adenoma. Immunohistochemical staining for key steroidogenic enzymes confirmed the adrenocortical origin without excessive hormone production. CONCLUSION: This is the first case of an ectopic adrenocortical adenoma in the renal hilum that caused gross hematuria without hormonal symptoms.

Increased Expression of Tripartite Motif (TRIM) 47 Is a Negative Prognostic Predictor in Human Prostate Cancer.

BACKGROUND: Many prognostic biomarkers associated with androgen signaling have been proposed in PC. The role of tripartite motif (TRIM) proteins remains unclear in PC. We investigated TRIM protein 47 (TRIM47) expression levels in human prostate tissues. METHODS: We performed immunohistochemistry using original TRIM47 antibody in prostate tissues obtained by radical prostatectomy (n = 105). Stained slides were evaluated for the proportion and staining intensity of immunoreactive cells. Total immunoreactivity (IR) scores (range, 0-8) were calculated as the sum of the proportion and intensity scores. TRIM47 expression levels were confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Associations between the clinicopathologic features of the patients and their TRIM47 status were analyzed. RESULTS: Western blot analysis validated the specificity of the anti-TRIM47 antibody in 293T cells. TRIM47 expression levels were found to be significantly increased in PC compared to benign tissues by both immunohistochemistry (P < .0001) and qRT-PCR (P = .003). Additionally, advanced pathologic stage (≥ T3b) was found to be associated with high TRIM47 IR scores (≥ 4; P = .04). Furthermore, high TRIM47 IR scores were also significantly correlated with worse cancer-specific survival rates in multivariate regression analyses (hazard ratio, 6.82; P = .016). CONCLUSION: The results of the present study indicated differential TRIM47 expression levels in human prostate tissues compared to benign tissues. Because high levels of TRIM47 expression were found to be a strong prognostic factor in PC, TRIM47 may represent a novel therapeutic target.

Abhydrolase domain containing 2, an androgen target gene, promotes prostate cancer cell proliferation and migration.

BACKGROUND: The androgen receptor (AR) plays a key role in the development of prostate cancer. AR signalling mediates the expression of androgen-responsive genes, which are involved in prostate cancer development and progression. Our previous chromatin immunoprecipitation study showed that the region of abhydrolase domain containing 2 (ABHD2) includes a functional androgen receptor binding site. In this study, we demonstrated that ABHD2 is a novel androgen-responsive gene that is overexpressed in human prostate cancer tissues. METHODS: The expression levels of ABHD2 in androgen-sensitive cells were evaluated by quantitative reverse transcription polymerase chain reaction and western-blot analyses. LNCaP and VCaP cells with ABHD2 overexpression or short interfering RNA (siRNA) knockdown were used for functional analyses. ABHD2 expression was examined in clinical samples of prostate cancer by immunohistochemistry. RESULTS: We showed that ABHD2 expression is increased by androgen in LNCaP and VCaP cells. This androgen-induced ABHD2 expression was diminished by bicalutamide. While stable expression of ABHD2 affected the enhancement of LNCaP cell proliferation and migration, siRNA-mediated ABHD2 knockdown suppressed cell proliferation and migration. In addition, the siRNA treatment significantly repressed the tumour growth derived from LNCaP cells in athymic mice. Immunohistochemical analysis of ABHD2 expression in tumour specimens showed a positive correlation of ABHD2 immunoreactivity with high Gleason score and pathological N stage. Moreover, patients with high immunoreactivity of ABHD2 showed low cancer-specific survival rates and a resistance to docetaxel-based chemotherapy. CONCLUSION: ABHD2 is a novel androgen-regulated gene that can promote prostate cancer growth and resistance to chemotherapy, and is a novel target for diagnosis and treatment of prostate cancer.

Efficacy of transurethral prostate enucleation by bipolar system for patients with benign prostatic hyperplasia.

BACKGROUND: The aim of this paper was to evaluate the efficacies and safety of transurethral prostate enucleation by bipolar system (TUEB) for the patients with benign prostatic hyperplasia (BPH). METHODS: We prospectively evaluated clinical outcomes of TUEB in 55 patients with BPH from July 2005 to January 2011. Mean ages of the patients were 69.2 years. International Prostate Symptom Score (IPSS), IPSS-quality of life (IPSS-QOL) were assessed before and 12 months after surgery. Serum PSA, maximal flow rate (MFR), and post-void residual (PVR) were also evaluated before and 6 and 12 months after surgery. RESULTS: The median prostate volumes and resection volumes were 64.1 g (interquartile range [IQR]: 48-87) and 34.4 g (25-60.2), respectively. The median operation time was 138.0 min (100.2-169.2). Total IPSS scores and IPSS-QOL were significantly improved (from 24 [17-31] to 5 [2-8] points, and from 6 [5-6] to 2 [1-2] points, both P<0.001). MFR and PVR were significantly improved 6 and 12 months after TUEB (from 6.2 [3.9-8.3] to 15.1 [10.5-20.9], and 14.6 [10.2-20.5] mL/s, P<0.0001, and from 151.5 [81.5-284.7] to 16.5 [0-30.5], and 6.0 [0-41.0] mL, P<0.0001, respectively). Serum PSA also significantly decreased, 6 and 12 months (from 7.5 [4.7-9.8] to 1.1 [0.5-1.5], and 0.6 [0.3-1.9] ng/mL, P<0.0001). Although hemoglobin decreased after operation, no case experienced blood transfusion. Three episodes of urinary tract infections, 14 cases of mild stress urinary incontinence, 2 cases of urinary retention were occurred transiently with recovery within 1 month after surgery. CONCLUSIONS: We identified favorable efficacy and safety of TUEB. TUEB appears to be another possibility in the treatment of BPH.

14-3-3ζ, a novel androgen-responsive gene, is upregulated in prostate cancer and promotes prostate cancer cell proliferation and survival.

PURPOSE: Androgen receptor is an essential transcriptional factor that contributes to the development and progression of prostate cancer. In this study, we investigated the androgen regulation and functional analysis of 14-3-3ζ in prostate cancer. EXPERIMENTAL DESIGN: Using chromatin immunoprecipitation (ChIP) combined with DNA microarray (ChIP-chip) analysis in LNCaP cells, we identified a functional androgen receptor-binding site in the downstream region of the 14-3-3ζ gene. Androgen regulation was examined by quantitative reverse transcription PCR and Western blot analysis. Prostate cancer cells stably expressing 14-3-3ζ and siRNA knockdown were used for functional analyses. We further examined 14-3-3ζ expression in clinical samples of prostate cancer by immunohistochemistry and quantitative reverse transcription PCR. RESULTS: Androgen-dependent upregulation of 14-3-3ζ was validated at the mRNA and protein levels. The 14-3-3ζ gene is favorable for cancer-cell survival, as its ectopic expression in LNCaP cells contributes to cell proliferation and the acquired resistance to etoposide-induced apoptosis. 14-3-3ζ expression was associated with androgen receptor transcriptional activity and prostate-specific antigen (PSA) mRNA expression. Immunoprecipitation indicated that 14-3-3ζ was associated with androgen receptor in the nucleus. Clinicopathologic studies further support the relevance of 14-3-3ζ in prostate cancers, as its higher expression is associated with malignancy and lymph node metastasis. CONCLUSIONS: 14-3-3ζ is a novel androgen-responsive gene that activates proliferation, cell survival, and androgen receptor transcriptional activity. 14-3-3ζ may facilitate the progression of prostate cancer.