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Inhibiting the activity of the androgen receptor (AR) is the cornerstone treatment for advanced prostate cancer. AR-targeted therapies are highly effective in slowing disease progression but are not curative. Failure of these therapies results in a disease state termed castration-resistant prostate cancer, which is associated with significant patient morbidity and mortality. In most cases, resistance to AR-targeted therapies arises due to alterations that reactivate the AR signalling axis. Interestingly, it has long been recognised that potent activation of AR with supraphysiological levels of androgens can suppress prostate cancer growth in both preclinicalmodels and patients. This intriguing paradox, where both inhibition and activation of AR have anti-cancer effects, is nowbeing harnessed clinically in the formof bipolar androgen therapy (BAT). This review describes mechanisms underlying the tumour-suppressive functions of AR in the context of potent androgenic stimulation and discusses howourmaturing understanding of these processes is influencing the clinical deployment of BAT. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer is the most common diagnosed tumor and the fifth cancer related death among men in Europe. Although several genetic alterations such as ERG-TMPRSS2 fusion, MYC amplification, PTEN deletion and mutations in p53 and BRCA2 genes play a key role in the pathogenesis of prostate cancer, specific gene alteration signature that could distinguish indolent from aggressive prostate cancer or may aid in patient stratification for prognosis and/or clinical management of patients with prostate cancer is still missing. Therefore, here, by a multi-omics approach we describe a prostate cancer carrying the fusion of TMPRSS2 with ERG gene and deletion of 16q chromosome arm. Results: We have observed deletion of KDM6A gene, which may represent an additional genomic alteration to be considered for patient stratification. The cancer hallmarks gene signatures highlight intriguing molecular aspects that characterize the biology of this tumor by both a high hypoxia and immune infiltration scores. Moreover, our analysis showed a slight increase in the Tumoral Mutational Burden, as well as an over-expression of the immune checkpoints. The omics profiling integrating hypoxia, ROS and the anti-cancer immune response, optimizes therapeutic strategies and advances personalized care for prostate cancer patients. Conclusion: The here data reported can lay the foundation for predicting a poor prognosis for the studied prostate cancer, as well as the possibility of targeted therapies based on the modulation of hypoxia, ROS, and the anti-cancer immune response. [ABSTRACT FROM AUTHOR]

Androgen receptor inhibitors are commonly used for prostate cancer treatment, but acquired resistance is a significant problem. Codeletion of RB and p53 is common in castration resistant prostate cancers, however they are difficult to target pharmacologically. To comprehensively identify gene loss events that contribute to enzalutamide response, we performed a genome-wide CRISPR knockout screen in LNCaP prostate cancer cells. This revealed novel genes implicated in resistance that are largely unstudied. Gene loss events that confer enzalutamide sensitivity are enriched for GSEA categories related to stem cell and epigenetic regulation. We investigated the myeloid lineage stem cell factor HOXA9 as a candidate gene whose loss promotes sensitivity to enzalutamide. Cancer genomic data reveals that HOXA9 overexpression correlates with poor prognosis and characteristics of advanced prostate cancer. In cell culture, HOXA9 depletion sensitizes cells to enzalutamide, whereas overexpression drives enzalutamide resistance. Combination of the HOXA9 inhibitor DB818 with enzalutamide demonstrates synergy. This demonstrates the utility of our CRISPR screen data in discovering new approaches for treating enzalutamide resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa), with high heterogeneity and poor prognosis, is one of the most common malignant tumors in men. Circular RNAs (circRNAs) have been identified in tumor progression and resistance to medication in numerous studies. However, the role of circ_0001047 in PCa is unclear. In this research, we found that circ_0001047 had low expression in PCa cells and tissues and was negatively correlated with testosterone secretion in vivo. Overexpression of circ_0001047 inhibited the proliferation, migration, invasion, and anti-apoptotic abilities of human PCa cells in vitro. Mechanistically, circ_0001047 promoted the expression of FKBP5 through sponge adsorption of miR-122-5p and then inhibited the proliferation, anti-apoptotic migration, and invasion abilities of PCa cells. In addition, overexpression of circ_0001047 enhanced the sensitivity of PCa cells to abiraterone by inhibiting AKT phosphorylation activation through upregulation of FKBP5/PHLPP1. This study revealed a novel mechanism by which circ_0001047 regulates PCa progression and treatment sensitivity via the miR-122-5p/FKBP5/PHLPP1/AKT axis. These findings deepen our comprehension of the molecular mechanisms in latent PCa progression and treatment resistance. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer is among prevalent cancers in men. Numerous strategies have been proposed to intervene with the important prostate cancer-related signaling pathways. Among the most promising strategies is CRISPR/Cas9 strategy. This strategy has been used to modify expression of a number of genes in prostate cancer cells. Aims: This review summarizes the most recent progresses in the application of CRISPR/Cas9 strategy in modification of prostate cancer-related phenotypes with an especial focus on pathways related to androgen receptor signaling. Conclusion: CRISPR/Cas9 technology has successfully targeted several genes in the prostate cancer cells. Moreover, the efficiency of this technique in reducing tumor burden has been tested in animal models of prostate cancer. Most of targeted genes have been related with the androgen receptor signaling. Targeted modulation of these genes have affected growth of castration-resistant prostate cancer. PI3K/AKT/mTOR signaling and immune response-related genes have been other targets that have been successfully modulated by CRISPR/Cas9 technology in prostate cancer. Based on the rapid translation of this technology into the clinical application, it is anticipated that novel treatments based on this technique change the outcome of this malignancy in future. [ABSTRACT FROM AUTHOR]

The impact of tumor focality on prostate cancer (PCa) prognosis has been addressed in several studies with conflicting results. Tumor foci from multifocal (MF) PCa can show highly heterogeneous molecular features. Our aim was to analyze the protein expression of PTEN, SPOP, SLC45A3, ETV1, ERG and the "triple hit" (ERG overexpression, PTEN plus SLC45A3 loss) in unifocal (UF) and MF PCa, to evaluate their value as prognostic markers according to focality, and the role of tumor heterogeneity in MF disease. PTEN, SPOP, SLC45A3, ETV1 and ERG immunohistochemical expression was evaluated in 185 PCa from 9 TMAs, 51 UF and 134 MF. In a subset of 69 MF cases, the dominant and secondary foci (DF and SF) were compared. Heterogeneity was considered when both tumor foci presented different expression patterns. Relationship with clinicopathological features was also analyzed. MF PCa was diagnosed in significantly younger patients when compared to UF ones (p = 0.007). ETV1 overexpression was associated with UF disease (p = 0.028). A shorter time to PSA recurrence was related to SLC45A3 wt expression in UF PCa (p = 0.052), and to SPOP expression loss (p = 0.043) or "triple hit" phenotype in MF PCa (p = 0.041). In MF cases, PTEN loss, SLC45A3 loss and "triple hit" phenotype were associated with the DF and had significant heterogeneity. In conclusion, our results indicate that UF and MF PCa have relevant and consistent molecular differences. The analysis of an immunohistochemical panel, composed by PTEN, SPOP, SLC45A3, ETV1 and ERG, could be useful to predict outcome in MF cases. [ABSTRACT FROM AUTHOR]

Androgen receptor signaling is crucial for the development of treatment resistance in prostate cancer. Among steroidogenic enzymes, 3β-hydroxysteroid dehydrogenases (3βHSDs) play critical roles in extragonadal androgen synthesis, especially 3βHSD1. Increased expression of 3βHSDs is observed in castration-resistant prostate cancer tumors compared with primary prostate tumors, indicating their involvement in castration resistance. Recent studies link 3βHSD1 to resistance to androgen receptor signaling inhibitors. The regulation of 3βHSD1 expression involves various factors, including transcription factors, microenvironmental influences, and posttranscriptional modifications. Additionally, the clinical significance of HSD3B1 genotypes, particularly the rs1047303 variant, has been extensively studied. The impact of HSD3B1 genotypes on treatment outcomes varies according to the therapy administered, suggesting the potential of HSD3B1 genotyping for personalized medicine. Targeting 3βHSDs may be a promising strategy for prostate cancer management. Overall, understanding the roles of 3βHSDs and their genetic variations may enable the development and optimization of novel treatments for prostate cancer. [ABSTRACT FROM AUTHOR]

Introduction: Prostate-specific antigen (PSA) plays an important role in the detection of prostate cancer. Although it has high sensitivity and low specificity, it is still used clinically. A biopsy is recommended if any abnormality is detected in PSA or digital rectal examination (DRE). Materials and Methods: Forty cases diagnosed as prostatic adenocarcinoma out of 109 biopsies submitted were included in the two-year duration study. The clinical parameters (age and serum PSA levels) and histopathological parameters (number of positive cores, tumor percentage, Gleason grade and score, glomeruloid architecture, and perineural and lymphovascular invasion) are noted. Results: The age of the patients ranged from 33 to 98 years with a mean age of 67.5 years. The PSA levels ranged from 1.5 to 381.2 ng/mL. Four cases (10%) showed a lower PSA level of <4 ng/mL. Fourteen cases (35%) showed a Gleason grade of 3 + 3. Ten cases (25%) had a tumor volume between 31 and 40%. Perineural invasion and lymphovascular invasion were seen in 13 (32.5%) and 4 (10%) cases, respectively. A weak correlation was seen between PSA levels and Gleason score (r = 0.243). No correlation was seen between PSA levels and tumor volume (r = 0.01). A moderate correlation was noted between the Gleason score and tumor volume (r = 0.629). Conclusion: Prostate cancer detected by biopsies is not uncommon with PSA levels of 4.0 ng/mL or less. Prevalence of prostate cancer is 36.6%. A weak correlation was seen between PSA levels and the Gleason score. Radical prostatectomies are required to compare pre-operative Gleason score and tumor percentage with post-operative Gleason score and tumor volume. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. Methods: We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. Results: Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1β production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1β and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1β, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth. Conclusions: Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Androgen receptor signaling inhibitors combined with androgen deprivation therapy have become the standard of care for metastatic castration-sensitive prostate cancer (mCSPC), regardless of tumor volume or risk. However, survival of approximately one-third of these patients has not improved, necessitating further treatment escalation. On the other hand, for patients with oligometastatic mCSPC, there is an emerging role for local radiation therapy. Although data remain scarce, it is expected that treatment of both primary tumor as well as metastasis-directed therapy may improve survival outcomes. In these patients, systemic therapy may be de-escalated to intermittent therapy. However, precise risk stratification is necessary for risk-based treatment escalation or de-escalation. In addition to risk stratification based on clinical parameters, research has been conducted to incorporate genomic and/or transcriptomic data into risk stratification. In future, an integrated risk model is expected to precisely stratify patients and guide treatment strategies. Here, we first review the transition of the standard treatment for mCSPC over the last decade and further discuss the newest concept of escalating or de-escalating treatment using a multi-modal approach based on the currently available literature. [ABSTRACT FROM AUTHOR]

Background: Prostate adenocarcinoma (PRAD) is the second leading cause of cancer-related deaths in men. High variability in DNA methylation and a high rate of large genomic rearrangements are often observed in PRAD. Results: To investigate the reasons for such high variance, we integrated DNA methylation, RNA-seq, and copy number alterations datasets from The Cancer Genome Atlas (TCGA), focusing on PRAD, and employed weighted gene co-expression network analysis (WGCNA). Our results show that only single cluster of co-expressed genes is associated with genomic and epigenomic instability. Within this cluster, TP63 and TRIM29 are key transcription regulators and are downregulated in PRAD. We discovered that TP63 regulates the level of enhancer methylation in prostate basal epithelial cells. TRIM29 forms a complex with TP63 and together regulates the expression of genes specific to the prostate basal epithelium. In addition, TRIM29 binds DNA repair proteins and prevents the formation of the TMPRSS2:ERG gene fusion typically observed in PRAD. Conclusion: Our study demonstrates that TRIM29 and TP63 are important regulators in maintaining the identity of the basal epithelium under physiological conditions. Furthermore, we uncover the role of TRIM29 in PRAD development. [ABSTRACT FROM AUTHOR]

Background: Treatment failure following androgen deprivation therapy (ADT) presents a significant challenge in the management of advanced prostate cancer. Thus, understanding the genetic factors influencing this process could facilitate the development of personalized treatments and innovative therapeutic strategies. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in controlling cell growth and tumorigenesis. We hypothesized that genetic variants within this pathway may affect the clinical outcomes of patients undergoing ADT for prostate cancer. Methods: We genotyped 399 single-nucleotide polymorphisms (SNPs) across 28 core PI3K/AKT pathway genes in a cohort of 630 patients with prostate cancer undergoing ADT. We assessed the potential association of the SNPs with patient survival. Functional analyses of the implicated genes were also performed to evaluate their effects on prostate cancer. Results: After multivariate Cox regression analysis and multiple testing correction, GABRB3 rs12591845 exhibited the most significant association with both overall and cancer-specific survivals (P < 0.003). A comprehensive pooled analysis of 16 independent gene expression datasets revealed elevated expression of GABRB3 in prostate cancer tissues compared to that in normal tissues (P < 0.001). Furthermore, gene set enrichment analysis unveiled differential enrichment of pathways such as myogenesis, interferon γ and α responses, and the MYC proto-oncogene pathway in tumors with elevated GABRB3 expression, implying a role for GABRB3 in prostate cancer. Conclusion: Our results suggest that rs12591845 could potentially serve as a valuable prognostic indicator for patients undergoing ADT. The potential role of GABRB3 in promoting prostate tumorigenesis is also highlighted. [ABSTRACT FROM AUTHOR]

Background: Although Black men are more likely than non‐Hispanic White men to develop and die from prostate cancer, limited data exist to guide prostate‐specific antigen (PSA) screening protocols in Black men. This study investigated whether the risk for prostate cancer was higher than expected among self‐identified Black than White veterans based on prebiopsy PSA level. Methods: Multivariable logistic regression models were estimated to predict the likelihood of prostate cancer diagnosis on first biopsy for 75,295 Black and 207,658 White male veterans. Self‐identified race, age at first PSA test, prebiopsy PSA, age at first biopsy, smoking status, statin use, and socioeconomic factors were used as predictors. The adjusted predicted probabilities of cancer detection on first prostate biopsy from the logistic models at different PSA levels were calculated. Results: After controlling for PSA and other covariates, Black veterans were 50% more likely to receive a prostate cancer diagnosis on their first prostate biopsy than White veterans (odds ratio [OR], 1.50; 95% CI, 1.47‐1.53; p <.001). At a PSA level of 4.0 ng/mL, the probability of prostate cancer for a Black man was 49% compared with 39% for a White man. This model indicated that Black veterans with a PSA of 4.0 ng/mL have an equivalent risk of prostate cancer as White veterans with a PSA of 13.4 ng/mL. Conclusions: The findings indicate that, at any given PSA level, Black men are more likely to harbor prostate cancer than White men. Prospective studies are needed to better evaluate risks and benefits of PSA screening in Black men and other high‐risk populations. At any given prostate‐specific antigen level, Black men have substantially higher risk of prostate cancer detection on their first biopsy compared with White men after accounting for socioeconomic factors, age, and prebiopsy prostate‐specific antigen. This difference was more pronounced among younger men. [ABSTRACT FROM AUTHOR]

Objective: Using multi-parametric magnetic resonance imaging (mpMRI) to identify patients with clinical T3a (cT3a) who were overestimated on mpMRI with final pathological T2 (pT2). To suggest that the neurovascular bundle (NVB) can be preserved by evaluating the characteristics of patients according to their pathological grade among cT3a prostate cancer (PCa) patients using mpMRI. Materials and methods: Patients who underwent robot-assisted laparoscopic radical prostatectomy (RALP) were retrospectively analyzed and those patients with clinical T3aN0M0 were enrolled. These enrolled patients were divided into a localized cancer group with pT2 PCa and a locally advanced group with pT3a or higher. Factors affecting the diagnosis of localized PCa after RALP in patients with cT3a PCa were evaluated. Results: Among the preoperative parameters of patients with cT3a PCa, the prostate specific antigen density (PSAD) (OR: 3.76, 95% CI: 1.85-7.64, p<0.001), international society of urological pathology (ISUP) grade (p<0.05), and index lesion size (OR: 1.44, 95% CI: 1.85-7.64, p<0.001) were significantly associated with pathological locally advanced PCa. Optimal cut-off values for prediction of pT3a or higher were 0.36 ng/mL2 for PSAD (sensitivity: 55.7%, specificity: 70.8%), 1.77 cm for index lesion size (sensitivity: 54.3%, specificity: 66.0%), and 2.5 for ISUP grading (sensitivity: 67.6%, specificity: 53.2%). For prediction of pT3a or higher among patients with cT3a PCa, a nomogram was developed using ISUP grade, index lesion size, and PSAD on prostate biopsy (area under the curve: 0.71, 95% CI: 0.670-0.754, p<0.001). PSAD less than 0.36 index lesion size less than 1.77 cm, and biopsy ISUP grade 1-2 are highly likely to indicate that there is no actual extracapsular extension in cT3a PCa patients. Conclusions: PSAD, ISUP, and index lesion size showed significant associations with the classification of pathologic localized and locally advanced PCa in patients with cT3a PCa. A nomogram including these features can predict the diagnosis of locally advanced PCa in patients with cT3a PCa. [ABSTRACT FROM AUTHOR]

This article explores the role of regulatory T cells (Tregs) in prostate cancer (PCa) and their impact on prognosis and treatment response. The researchers found that Tregs can be divided into two subtypes: TregR, which is associated with a poor prognosis, immunosuppression, and resistance to therapy, and TregP, which has the opposite characteristics. TregR showed higher expression of TGF-β and mutations in the TP53 and PIK3CA genes, which may contribute to therapy resistance. The study suggests that targeting TGF-β and the PI3K-AKT-mTOR pathway may improve treatment outcomes for TregR PCa. [Extracted from the article]

Prostate transmembrane androgen inducible protein 1 (PMEPA1) can promote or inhibit prostate cancer cell growth based on the cancer cell response to the androgen receptor (AR). Further, it can be upregulated by transforming growth factor (TGF), which downregulates transforming growth factor-b (TGF-b) signaling by interfering with R-Smad phosphorylation to facilitate TGF-b receptor degradation. Studies have indicated the increased expression of PMEPA1 in some solid tumors and its functioning as a regulator of multiple signaling pathways. This review highlights the multiple potential signaling pathways associated with PMEPA1 and the role of the PMEPA1 gene in regulating prognosis, including transcriptional regulation and epithelial mesenchymal transition (EMT). Moreover, the relevant implications in and outside tumors, for example, as a biomarker and its potential functions in lysosomes have also been discussed. [ABSTRACT FROM AUTHOR]

Patients with metastatic prostate cancer, especially in the castrate-resistant setting, have a poor prognosis. Many agents have been approved for metastatic prostate cancer, such as androgen receptor pathway inhibitors, taxane-based chemotherapy, radiopharmaceuticals, and immunotherapy. However, prostate cancer remains the leading cause of cancer deaths in nonsmoking men. Fortunately, many more novel agents are under investigation. We provide an overview of the broad group of novel therapies for metastatic prostate cancer, with an emphasis on active and recruiting clinical trials that have been recently published and/or presented at national or international meetings. The future for patients with metastatic prostate cancer is promising, with further development of novel therapies such as radiopharmaceuticals. Based on a growing understanding of prostate cancer biology, novel agents are being designed to overcome resistance to approved therapies. There are many trials using novel agents either as monotherapy or in combination with already approved agents with potential to further improve outcomes for men with advanced prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: The synergy of combining androgen receptor-signaling inhibition (ARSI) to radiotherapy (RT) in prostate cancer has been largely attributed to non-homologous end joining (NHEJ) inhibition. However, this mechanism is unlikely to explain recently observed trial results that demonstrated the sequencing of ARSI and RT significantly impacts clinical outcomes, with adjuvant ARSI following RT yielding superior outcomes to neoadjuvant/concurrent therapy. We hypothesized this is driven by differential effects on AR-signaling and alternative DNA repair pathway engagement based on ARSI/RT sequencing. Methods: We explored the effects of ARSI sequencing with RT (neoadjuvant vs concurrent vs adjuvant) in multiple prostate cancer cell lines using androgen-deprived media and validation with the anti-androgen enzalutamide. The effects of ARSI sequencing were measured with clonogenic assays, AR-target gene transcription and translation quantification, cell cycle analysis, DNA damage and repair assays, and xenograft animal validation studies. Results: Adjuvant ARSI after RT was significantly more effective at killing colony forming cells and decreasing the transcription and translation of downstream AR-target genes across all prostate cancer models evaluated. These results were reproduced in xenograft studies. The differential effects of ARSI sequencing were not fully explained by NHEJ inhibition alone, but by the additional disruption of homologous recombination specifically with adjuvant sequencing of ARSI. Conclusion: We demonstrate that altered sequencing of ARSI and RT mediates differential anti-AR-signaling and anti-cancer effects, with the greatest benefit from adjuvant ARSI following RT. These results, combined with our prior clinical findings, support the superiority of an adjuvant-based sequencing approach when using ARSI with RT. [ABSTRACT FROM AUTHOR]

The study aims to synthesize all available prospective comparative studies and reports the latest systematic analysis and updated evidence comparing robot-assisted radical prostatectomy (RARP) with open radical prostatectomy (ORP) for perioperative, functional, and oncological outcomes in patients with clinically localized prostate cancer (PCa). PubMed, Embase, Web of Science, and the Cochrane Library were retrieved up to March 2023. Only randomized controlled trials (RCTs) and prospective comparative studies were included, and weighted mean differences (WMD) and odds ratios (OR) were used to evaluate the pooled results. Twenty-one articles were included in the present meta-analysis. The results indicated that compared to ORP, RARP had longer operative time (OT) (WMD: 51.41 min; 95%CI: 28.33, 74.48; p < 0.0001), reduced blood loss (WMD: −516.59 mL; 95%CI: −578.31, −454.88; p < 0.00001), decreased transfusion rate (OR: 0.23; 95%CI: 0.18, 0.30; p < 0.00001), shorter hospital stay (WMD: −1.59 days; 95%CI: −2.69, −0.49; p = 0.005), fewer overall complications (OR: 0.61; 95%CI: 0.45, 0.83; p = 0.001), and higher nerve sparing rate (OR: 1.64; 95%CI: 1.26, 2.13; p = 0.0003), as well as was more beneficial to postoperative erectile function recovery and biochemical recurrence (BCR). However, no significant disparities were noted in major complications, postoperative urinary continence recovery, or positive surgical margin (PSM) rates. RARP was superior to ORP in terms of hospital stay, blood loss, transfusion rate, complications, nerve sparing, postoperative erectile function recovery, and BCR. It is a safe and effective surgical approach to the treatment of clinically localized PCa. [ABSTRACT FROM AUTHOR]

Introduction: African American (AA) men exhibited 2.3-fold higher PCa incidence and 1.7-fold higher PCa mortality rates when compared to the European American (EA) men. Besides the socioeconomic factors, emerging evidence has highlighted that biological risk factors may play critical roles in the AA PCa disparities. Previously, we have shown that downregulated miR-99b-5p and upregulated mTOR cooperatively promotes the AA PCa aggressiveness and drug resistance. Methods: In this study, we aimed to explore the miR-99b-5p/mTOR/AR/ SMARCD1 signaling axis in AA PCa aggressiveness. The analyses used in the study included immunofluorescence, western blot, in-vitro functional assays (TUNEL, colony forming, and MTT), and chromatin immunoprecipitation (ChIP)- qPCR assays in 2D and/or 3D culture model of EA PCa and AA PCa cell lines. Results: Specifically, the immunofluorescence staining, and western blot analysis has revealed that nuclear mTOR, AR, and SMARCD1 were highly expressed in AA PCa (MDA PCa 2b) compared to EA PCa (LNCaP) cell line. Western blot analysis further revealed that miR-99b-5p inhibited protein levels of mTOR, AR/AR-V7 and SMARCD1 in cytoplasm and nuclei of EA and AA PCa. The in-vitro functional (MTT, TUNEL, and clonogenic) assays have demonstrated that miR-99b-5p effectively inhibited cell proliferation/survival and induced cell apoptosis in EA and AA PCa cells. Moreover, combination of miR-99b-5p and enzalutamide (Enz) synergistically enhances the cytotoxicity against aggressive AA PCa and castrationresistant prostate cancer (CRPC). mTOR ChIP-qPCR assays further demonstrated that miR-99b-5p or miR-99b-5p/Enz significantly reduces the recruitment of mTOR to the genes involved in the metabolic reprogramming in CRPC. Discussion: Taken together, miR-99b-5p may function as an epigenomic driver to modulate the mTOR/AR/SMARCD1 signaling axis in AA PCa and resistant CRPC. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second most common cancer in males worldwide. The risk stratification of PCa is mainly based on morphological examination. Here we analyzed the proteome of 667 tumor samples from 487 Chinese PCa patients and characterized 9576 protein groups by PulseDIA mass spectrometry. Then we developed a pathway activity-based classifier concerning 13 proteins from seven pathways, and dichotomized the PCa patients into two subtypes, namely PPS1 and PPS2. PPS1 is featured with enhanced innate immunity, while PPS2 with suppressed innate immunity. This classifier exhibited a correlation with PCa progression in our cohort and was further validated by two published transcriptome datasets. Notably, PPS2 was significantly correlated with poor biochemical recurrence (BCR)/metastasis-free survival (log-rank P-value < 0.05). The PPS2 was also featured with cell proliferation activation. Together, our study presents a novel pathway activity-based stratification scheme for PCa. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCA) is the fifth leading cause of cancer-related deaths worldwide, with limited treatment options in the advanced stages. The immunosuppressive tumor microenvironment (TME) of PCA results in lower sensitivity to immunotherapy. Although molecular subtyping is expected to offer important clues for precision treatment of PCA, there is currently a shortage of dependable and effective molecular typing methods available for clinical practice. Therefore, we aim to propose a novel stemness-based classification approach to guide personalized clinical treatments, including immunotherapy. Methods: An integrative multi-omics analysis of PCA was performed to evaluate stemness-level heterogeneities. Unsupervised hierarchical clustering was used to classify PCAs based on stemness signature genes. To make stemness-based patient classification more clinically applicable, a stemness subtype predictor was jointly developed by using four PCA datasets and 76 machine learning algorithms. Results: We identified stemness signatures of PCA comprising 18 signaling pathways, by which we classified PCA samples into three stemness subtypes via unsupervised hierarchical clustering: low stemness (LS), medium stemness (MS), and high stemness (HS) subtypes. HS patients are sensitive to androgen deprivation therapy, taxanes, and immunotherapy and have the highest stemness, malignancy, tumor mutation load (TMB) levels, worst prognosis, and immunosuppression. LS patients are sensitive to platinum-based chemotherapy but resistant to immunotherapy and have the lowest stemness, malignancy, and TMB levels, best prognosis, and the highest immune infiltration. MS patients represent an intermediate status of stemness, malignancy, and TMB levels with a moderate prognosis. We further demonstrated that these three stemness subtypes are conserved across pan-tumor. Additionally, the 9-gene stemness subtype predictor we developed has a comparable capability to 18 signaling pathways to make tumor diagnosis and to predict tumor recurrence, metastasis, progression, prognosis, and efficacy of different treatments. Conclusions: The three stemness subtypes we identified have the potential to be a powerful tool for clinical tumor molecular classification in PCA and pan-cancer, and to guide the selection of immunotherapy or other sensitive treatments for tumor patients. [ABSTRACT FROM AUTHOR]

Most genitourinary tract cancers have a negative impact on male fertility. Although testicular cancers have the worst impact, other tumors such as prostate, bladder, and penis are diagnosed early and treated in relatively younger patients in which couple fertility can be an important concern. The purpose of this review is to highlight both the pathogenetic mechanisms of damage to male fertility in the context of the main urological cancers and the methods of preserving male fertility in an oncological setting, in light of the most recent scientific evidence. A systematic review of available literature was carried out on the main scientific search engines, such as PubMed, Clinicaltrials.Gov, and Google scholar. Three hundred twenty-five relevant articles on this subject were identified, 98 of which were selected being the most relevant to the purpose of this review. There is a strong evidence in literature that all of the genitourinary oncological therapies have a deep negative impact on male fertility: orchiectomy, partial orchiectomy, retroperitoneal lymphadenectomy (RPLND), radical cystectomy, prostatectomy, penectomy, as well as radiotherapy, chemotherapy, and hormonal androgen suppression. Preservation of fertility is possible and includes cryopreservation, hormonal manipulation with GnRH analogs before chemotherapy, androgen replacement. Germ cell auto transplantation is an intriguing strategy with future perspectives. Careful evaluation of male fertility must be a key point before treating genitourinary tumors, taking into account patients' age and couples' perspectives. Informed consent should provide adequate information to the patient about the current state of his fertility and about the balance between risks and benefits in oncological terms. Standard approaches to genitourinary tumors should include a multidisciplinary team with urologists, oncologists, radiotherapists, psycho-sexologists, andrologists, gynecologists, and reproductive endocrinologists. [ABSTRACT FROM AUTHOR]

Clinical and genomic features of prostate cancer (PCa) vary considerably between Asian and Western populations. PTEN loss is the most frequent abnormality in intraductal carcinoma of the prostate (IDC‐P) in Western populations. However, its prevalence and significance in Asian populations have not yet been well studied. In the present study, we evaluated PTEN expression in IDC‐P in a Japanese population and its association with ERG expression. This study included 45 and 59 patients with PCa with and without IDC‐P, respectively, who underwent radical prostatectomy. PTEN loss was observed in 10 patients with PCa with IDC‐P (22%) and nine patients with PCa without IDC‐P (17%). ERG expression was relatively frequent in patients with PCa with PTEN loss, although a significant difference was not observed. The co‐occurrence of PTEN loss and ERG expression was observed in four patients with PCa with IDC‐P and one without IDC‐P. PTEN loss and ERG expression did not affect progression‐free survival, regardless of the presence of IDC‐P. The frequency of PTEN loss in IDC‐P is lower in Asian patients than in Western patients. Our results indicate that mechanisms underlying IDC‐P in Asian populations are different from those of Western populations. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a non-cutaneous malignancy in males with wide variation in incidence rates across the globe. It is the second most reported cause of cancer death. Its etiology may have been linked to genetic polymorphisms, which are not only dominating cause of malignancy casualties but also exerts significant effects on pharmacotherapy outcomes. Although many therapeutic options are available, but suitable candidates identified by useful biomarkers can exhibit maximum therapeutic efficacy. The single-nucleotide polymorphisms (SNPs) reported in androgen receptor signaling genes influence the effectiveness of androgen receptor pathway inhibitors and androgen deprivation therapy. Furthermore, SNPs located in genes involved in transport, drug metabolism, and efflux pumps also influence the efficacy of pharmacotherapy. Hence, SNPs biomarkers provide the basis for individualized pharmacotherapy. The pharmacotherapeutic options for PCa include hormonal therapy, chemotherapy (Docetaxel, Mitoxantrone, Cabazitaxel, and Estramustine, etc.), and radiotherapy. Here, we overview the impact of SNPs reported in various genes on the pharmacotherapy for PCa and evaluate current genetic biomarkers with an emphasis on early diagnosis and individualized treatment strategy in PCa. [ABSTRACT FROM AUTHOR]

The introduction of novel therapeutic agents for advanced prostate cancer has led to a wide range of treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC). In the past decade, new treatment options for mCRPC, including abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, radium-223, 177Lu-PSMA-617, and Olaparib, have demonstrated a survival benefit in phase 3 trials. Bone-modifying agents have become part of the overall treatment strategy for mCRPC, in which denosumab and zoledronic acid reduce skeletal-related events. Recently, androgen receptor-signaling inhibitors (ARSIs) and docetaxel have been used upfront against metastatic castration-sensitive prostate cancer. Further, triplet therapy with ARSI, docetaxel, and androgen deprivation therapy is emerging. However, cross-resistance may occur between these treatments, and the optimal treatment sequence must be considered. The sequential administration of ARSIs, such as abiraterone and enzalutamide, is associated with limited efficacy; however, cabazitaxel is effective for patients with mCRPC who were previously treated with docetaxel and had disease progression during treatment with ARSI. Radioligand therapy with 177Lu-PSMA-617 is a new effective class of therapy for patients with advanced PSMA-positive mCRPC. Tumors with gene alterations that affect homologous recombination repair, such as BRCA1 and BRCA2 alterations, are sensitive to poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitors in mCRPC. This review sought to highlight recent advances in systemic therapy for mCRPC and strategies to support patient selection and treatment sequencing. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is one of the most common cancers in males. A significant proportion of PCs bear TMPRSS2-ETS translocation and overexpress ERG transcription factor, allowing classification into ERG+ and ERG-- groups, which differ in several features including the tumor microenvironment. The aim of the study was to verify whether they differ in expression of the miRNA in the microenvironment. The material consisted of 150 radical prostatectomies. Immunohistochemistry (IHC) for ERG was done using a routine method. FISH for TMPRSS2-ETS translocation was done with a ZytoLight SPEC ERG/TMPRSS2 TriCheck Probe. From each case, a representative section was selected, and tumor and non-tumor were micro-dissected with the LMD7000 device. RNA was isolated using the RNeasy Mini Kit system (Qiagen) and miRNA libraries were prepared with the NEBNext Multiplex Small RNA Library Prep Set for Illumina and their sequencing was performed on the NexSeq 500. Statistical analysis was done with Statistica and R software. When analyzing the expression of miRNAs some differences could be seen, but after correction for multiple comparisons was applied, these were found to be nonsignificant. [ABSTRACT FROM AUTHOR]

Robot-assisted radical prostatectomy (RARP) has become one of the standard radical treatments for prostate cancer (PCa). A retrospective single-center cohort study was conducted on patients with PCa who underwent RARP at Gifu University Hospital between September 2017 and September 2022. In this study, patients were classified into three groups based on the National Comprehensive Cancer Network risk classification: low/intermediate-risk, high-risk, and very-high-risk groups. Patients with high- and very-high-risk PCa who were registered in the study received neoadjuvant chemohormonal therapy prior to RARP. Biochemical recurrence-free survival (BRFS) after RARP in patients with PCa was the primary endpoint of this study. The secondary endpoint was the relationship between biochemical recurrence (BCR) and clinical covariates. We enrolled 230 patients with PCa in our study, with a median follow-up of 17.0 months. When the time of follow-up was over, 19 patients (8.3%) had BCR, and the 2 years BRFS rate for the enrolled patients was 90.9%. Although there was no significant difference in BRFS between the low- and intermediate-risk group and the high/very-high-risk group, the 2 years BRFS rate was 100% in the high-risk group and 68.3% in the very-high-risk group (P = 0.0029). Multivariate analysis showed that positive surgical margins were a significant predictor of BCR in patients with PCa treated with RARP. Multimodal therapies may be necessary to improve the BCR in patients with very-high-risk PCa. [ABSTRACT FROM AUTHOR]

Introduction: Prostate cancer (PCa) is the most common type of cancer in males, and the metastatic form is a leading cause of death worldwide. There are currently no curative treatments for this subset of patients. To decrease the mortality of this disease, greater focus must be placed on developing therapeutics to reduce metastatic spread. We focus on dissemination to the bone since this is both the most common site of metastatic spread and associated with extreme pain and discomfort for patients. Our strategy is to exploit microRNAs (miRNAs) to disrupt the spread of primary PCa to the bone. Methods: PCa cell lines were transduced to overexpress microRNA-379 (miR-379). These transduced PCa cells were assessed using cell growth, migration, colony formation and adhesion assays. We also performed in vivo intracardiac injections to look at metastatic spread in NSG mice. A cytokine array was also performed to identify targets of miR-379 that may drive metastatic spread. Results: PCa cells with increased levels of miR-379 showed a significant decrease in proliferation, migration, colony formation, and adhesion to bone cells in vitro. In vivo miR-379 overexpression in PC3 cells significantly decreased metastatic spread to bone and reduced levels of miR-379 were seen in patients with metastases. We identified GDF-15 to be secreted from osteoblasts when grown in conditioned media from PCa cells with reduced miR-379 levels. Discussion: Taken together, our in vitro and in vivo functional assays support a role for miR-379 as a tumour suppressor. A potential mechanism is unravelled whereby miR-379 deregulation in PCa cells affects the secretion of GDF-15 from osteoblasts which in turn facilitates the metastatic establishment in bone. Our findings support the potential role of miR-379 as a therapeutic solution for prostate cancer. [ABSTRACT FROM AUTHOR]

Introduction: Chronological aging is a well-recognized diagnostic and prognostic factor in multiple cancer types, yet the role of biological aging in manifesting cancer progression has not been fully explored yet. Methods: Given the central role of chronological aging in prostate cancer and AML incidence, here we investigate a tissue-specific role of biological aging in prostate cancer and AML progression. We have employed Cox proportional hazards modeling to associate biological aging genes with cancer progression for patients from specific chronological aging groups and for patients with differences in initial cancer aggressiveness. Results: Our prostate cancer-specific investigations nominated four biological aging genes (CD44, GADD45B, STAT3, GFAP) significantly associated with time to disease progression in prostate cancer in Taylor et al. patient cohort. Stratified survival analysis on Taylor dataset and validation on an independent TCGA and DKFZ PRAD patient cohorts demonstrated ability of these genes to predict prostate cancer progression, especially for patients with higher Gleason score and for patients younger than 60 years of age. We have further tested the generalizability of our approach and applied it to acute myeloid leukemia (AML). Our analysis nominated three AML-specific biological aging genes (CDC42EP2, CDC42, ALOX15B) significantly associated with time to AML overall survival, especially for patients with favorable cytogenetic risk score and for patients older than 56 years of age. Discussion: Comparison of the identified PC and AML markers to genes selected at random and to known markers of progression demonstrated robustness of our results and nominated the identified biological aging genes as valuable markers of prostate cancer and AML progression, opening new avenues for personalized therapeutic management and potential novel treatment investigations. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is one of the most common cancers in males and the fifth leading reason of death. Age, ethnicity, family history, and genetic defects are major factors that determine the aggressiveness and lethality of PC. The African population is at the highest risk of developing high-grade PC. It can be challenging to distinguish between low-risk and high-risk patients due to the slow progression of PC. Prostate-specific antigen (PSA) is a revolutionary discovery for the identification of PC. However, it has led to an increase in over diagnosis and over treatment of PC in the past few decades. Even if modifications are made to the standard PSA testing, the specificity has not been found to be significant. Our understanding of PC genetics and proteomics has improved due to advances in different fields. New serum, urine, and tissue biomarkers, such as PC antigen 3 (PCA3), have led to various new diagnostic tests, such as the prostate health index, 4K score, and PCA3. These tests significantly reduce the number of unnecessary and repeat biopsies performed. Chemotherapy, radiotherapy, and prostatectomy are standard treatment options. However, newer novel hormone therapy drugs with a better response have been identified. Androgen deprivation and hormonal therapy are evolving as new and better options for managing hormone-sensitive and castration-resistant PC. This review aimed to highlight and discuss epidemiology, various risk factors, and developments in PC diagnosis and treatment regimens. [ABSTRACT FROM AUTHOR]

Background: Nowadays, the incidence rate of advanced and metastatic prostate cancer at the first time of diagnosis grows higher in China yearly. At present, androgen deprivation therapy (ADT) is the primary treatment of advanced prostate cancer. However, after several years of ADT, most patients will ultimately progress to castration-resistant prostate cancer (CRPC). Previous studies mainly focus on Caucasian and very few on East Asian patients. Methods: In this study, the pre- and post-ADT tumor samples were collected from five Chinese patients with advanced prostate cancer. The whole-exome sequencing, tumor heterogeneity, and clonal evolution pattern were analyzed. Results: The results showed that the gene mutation pattern and heterogeneity changed significantly after androgen deprivation therapy. Tumor Mutational Burden (TMB) and Copy Number Alteration (CNA) were substantially reduced in the post-treatment group, but the Mutant-allele tumor heterogeneity (MATH), Socio-Demographic Index (SDI), Intratumor heterogeneity (ITH), and weighted Genome Instability Index (wGII) had no significant difference. According to the clone types and characteristics, the presence of main clones in five pre-and post-treatment samples, the clonal evolution pattern can be further classified into two sub-groups (the Homogeneous origin clonal model or the Heterogeneous origin clonal model). The Progression-free survival (PFS) of the patients with the "Homogeneous origin clonal model" was shorter than the "Heterogeneous origin clonal model". The longer PFS might relate to MUC7 and MUC5B mutations repaired. ZNF91 mutation might be responsible for resistance to ADT resistance. Conclusion: Our findings revealed potential genetic regulators to predict the castration resistance and provide insights into the castration resistance processes in advanced prostate cancer. The crosstalk between clonal evolution patterns and tumor microenvironment may also play a role in castration resistance. A multicenter-research including larger populations with different background are needed to confirm our conclusion in the future. [ABSTRACT FROM AUTHOR]

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. It is characterized by the loss of androgen receptor (AR) signaling in neuroendocrine transdifferentiation, and finally, resistance to AR-targeted therapy. With the application of a new generation of potent AR inhibitors, the incidence of NEPC is gradually increasing. The molecular mechanism of neuroendocrine differentiation (NED) after androgen deprivation therapy (ADT) remains largely unclear. In this study, using NEPC-related genome sequencing database analyses, we screened RACGAP1, a common differentially expressed gene. We investigated RACGAP1 expression in clinical prostate cancer specimens by IHC. Regulated pathways were examined by Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation, and immunoprecipitation assays. The corresponding function of RACGAP1 in prostate cancer was analyzed by CCK-8 and Transwell assays. The changes of neuroendocrine markers and AR expression in C4-2-R and C4-2B-R cells were detected in vitro. We confirmed that RACGAP1 contributed to NE transdifferentiation of prostate cancer. Patients with high tumor RACGAP1 expression had shorter relapse-free survival time. The expression of RACGAP1 was induced by E2F1. RACGAP1 promoted neuroendocrine transdifferentiation of prostate cancer by stabilizing EZH2 expression in the ubiquitin-proteasome pathway. Moreover, overexpression of RACGAP1 promoted enzalutamide resistance of castration-resistant prostate cancer (CRPC) cells. Our results showed that the upregulation of RACGAP1 by E2F1 increased EZH2 expression, which drove NEPC progression. This study explored the molecular mechanism of NED and may provide novel methods and ideas for targeted therapy of NEPC. [ABSTRACT FROM AUTHOR]

Prostate cancer (CaP) remains the second leading cause of cancer-related mortality in American men. Systemic treatments for metastatic CaP, which causes the majority of deaths, include androgen deprivation therapy and chemotherapy. These treatments induce remissions but do not cure CaP. Novel and functionally diverse therapeutic targets that control the cell biology that drives aggressive CaP progression are needed to overcome treatment resistance. Because signal transduction that mediates CaP cell behavior is tightly regulated by phosphorylation, kinases have attracted interest as alternative targets for CaP treatments. Here, we examine emerging evidence from recent NextGen sequencing and (phospho) proteomics analyses on clinical CaP specimens that were obtained during lethal disease progression to determine the role of deregulated kinase action in CaP growth, treatment resistance, and recurrence. We provide an overview of kinases that are impacted by gene amplification, gene deletion or somatic mutations during the progression from localized treatment-naïve CaP to metastatic castration-resistant CaP or neuroendocrine CaP, and the potential impact of such alterations on aggressive CaP behavior and treatment efficacy. Furthermore, we review knowledge on alterations in the phosphoproteome that occur during the progression to treatment-resistant CaP, the molecular mechanisms in the control of these changes, and the signal transduction associated with them. Finally, we discuss kinase inhibitors under evaluation in CaP clinical trials and the potential, challenges, and limitations to moving knowledge on the CaP kinome forward to new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa. [ABSTRACT FROM AUTHOR]

Background: Aberrant somatic genomic alteration including copy number amplification is a hallmark of cancer genomes. We previously profiled genomic landscapes of prostate cancer (PCa), yet the underlying causal genes with prognostic potential has not been defined. It remains unclear how a somatic genomic event cooperates with inherited germline variants contribute to cancer predisposition and progression. Methods: We applied integrated genomic and clinical data, experimental models and bioinformatic analysis to identify GATA2 as a highly prevalent metastasis-associated genomic amplification in PCa. Biological roles of GATA2 in PCa metastasis was determined in vitro and in vivo. Global chromatin co-occupancy and co-regulation of GATA2 and SMAD4 was investigated by coimmunoprecipitation, ChIP-seq and RNA-seq assays. Tumor cellular assays, qRT-PCR, western blot, ChIP, luciferase assays and CRISPR-Cas9 editing methods were performed to mechanistically understand the cooperation of GATA2 with SMAD4 in promoting TGFβ1 and AR signaling and mediating inherited PCa risk and progression. Results: In this study, by integrated genomics and experimental analysis, we identified GATA2 as a prevalent metastasis-associated genomic amplification to transcriptionally augment its own expression in PCa. Functional experiments demonstrated that GATA2 physically interacted and cooperated with SMAD4 for genome-wide chromatin co-occupancy and co-regulation of PCa genes and metastasis pathways like TGFβ signaling. Mechanistically, GATA2 was cooperative with SMAD4 to enhance TGFβ and AR signaling pathways, and activated the expression of TGFβ1 via directly binding to a distal enhancer of TGFβ1. Strinkingly, GATA2 and SMAD4 globally mediated inherited PCa risk and formed a transcriptional complex with HOXB13 at the PCa risk-associated rs339331/6q22 enhancer, leading to increased expression of the PCa susceptibility gene RFX6. Conclusions: Our study prioritizes causal genomic amplification genes with prognostic values in PCa and reveals the pivotal roles of GATA2 in transcriptionally activating the expression of its own and TGFβ1, thereby co-opting to TGFβ1/SMAD4 signaling and RFX6 at 6q22 to modulate PCa predisposition and progression. [ABSTRACT FROM AUTHOR]

Whether TMPRSS2-ERG fusion and TP53 gene alteration coordinately promote prostate cancer (PCa) remains unclear. Here we demonstrate that TMPRSS2-ERG fusion and TP53 mutation / deletion co-occur in PCa patient specimens and this co-occurrence accelerates prostatic oncogenesis. p53 gain-of-function (GOF) mutants are now shown to bind to a unique DNA sequence in the CTNNB1 gene promoter and transactivate its expression. ERG and β-Catenin co-occupy sites at pyrimidine synthesis gene (PSG) loci and promote PSG expression, pyrimidine synthesis and PCa growth. β-Catenin inhibition by small molecule inhibitors or oligonucleotide-based PROTAC suppresses TMPRSS2-ERG- and p53 mutant-positive PCa cell growth in vitro and in mice. Our study identifies a gene transactivation function of GOF mutant p53 and reveals β-Catenin as a transcriptional target gene of p53 GOF mutants and a driver and therapeutic target of TMPRSS2-ERG- and p53 GOF mutant-positive PCa. TP53 alteration and TMPRSS2-ERG fusion are often found together in prostate cancer. Here, the authors show that gain-of-function mutant p53 collaborates with ERG proto-oncogene to drive prostate cancer tumourigenesis by activating beta-catenin expression and afterwards pyrimidine synthesis. [ABSTRACT FROM AUTHOR]

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N7-methylguanosine (m7G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m7G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m7G tRNA methylation in cancer cell translation control and tumour biology. [ABSTRACT FROM AUTHOR]

Background: ST6GALNAC family members function as sialyltransferases and have been implicated in cancer progression. However, their aberrant expression levels, prognostic values and specific roles in metastatic prostate cancer (PCa) remain largely unclear. Methods: Two independent public datasets (TCGA-PRAD and GSE21032), containing 648 PCa samples in total, were employed to comprehensively examine the mRNA expression changes of ST6GALNAC family members in PCa, as well as their associations with clinicopathological parameters and prognosis. The dysregulation of ST6GALNAC5 was further validated in a mouse PCa model and human PCa samples from our cohort (n = 64) by immunohistochemistry (IHC). Gene Set Enrichment Analysis, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and drug sensitivity analyses were performed to enrich the biological processes most related to ST6GALNAC5. Sulforhodamine B, transwell, luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to examine the PCa cell proliferation, invasion and transcriptional regulation, respectively. Results: Systematical investigation of six ST6GALNAC family members in public datasets revealed that ST6GALNAC5 was the only gene consistently and significantly upregulated in metastatic PCa, and ST6GALNAC5 overexpression was also positively associated with Gleason score and predicted poor prognosis in PCa patients. IHC results showed that (1) ST6GALNAC5 protein expression was increased in prostatic intraepithelial neoplasia and further elevated in PCa from a PbCre;PtenF/F mouse model; (2) overexpressed ST6GALNAC5 protein was confirmed in human PCa samples comparing with benign prostatic hyperplasia samples from our cohort (p < 0.001); (3) ST6GALNAC5 overexpression was significantly correlated with perineural invasion of PCa. Moreover, we first found transcription factor GATA2 positively and directly regulated ST6GALNAC5 expression at transcriptional level. ST6GALNAC5 overexpression could partially reverse GATA2-depletion-induced inhibition of PCa cell invasion. The GATA2-ST6GALNAC5 signature exhibited better prediction on the poor prognosis in PCa patients than GATA2 or ST6GALNAC5 alone. Conclusions: Our results indicated that GATA2-upregulated ST6GALNAC5 might serve as an adverse prognostic biomarker promoting prostate cancer cell invasion. [ABSTRACT FROM AUTHOR]

Since the theory of modern anatomical partitioning of the prostate was proposed, the differences in the incidence and pathological parameters of prostate cancer between the peripheral zone and transition zone have been gradually revealed. It suggests that there are differences in the pathogenic pathways and molecular biology of prostate cancer between different regions of origin. Over the past decade, advances in sequencing technologies have revealed more about molecules, genomes, and cell types specific to the peripheral and transitional zones. In recent years, the innovation of spatial imaging and multiple-parameter magnetic resonance imaging has provided new technical support for the zonal study of prostate cancer. In this work, we reviewed all the research results and the latest research progress in the study of prostate cancer in the past two decades. We summarized and proposed several vital issues and focused directions for understanding the differences between peripheral and transitional zones in prostate cancer. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, and the development of castrate-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-related mortality. While CRPC typically develops through a gain in androgen receptor (AR) signaling, a subset of CRPC will lose reliance on the AR. This process involves genetic, epigenetic, and hormonal changes that promote cellular plasticity, leading to AR-indifferent disease, with neuroendocrine prostate cancer (NEPC) being the quintessential example. NEPC is enriched following treatment with second-generation antiandrogens and exhibits resistance to endocrine therapy. Loss of RB1, TP53, and PTEN expression and MYCN and AURKA amplification appear to be key drivers for NEPC differentiation. Epigenetic modifications also play an important role in the transition to a neuroendocrine phenotype. DNA methylation of specific gene promoters can regulate lineage commitment and differentiation. Histone methylation can suppress AR expression and promote neuroendocrinespecific gene expression. Emerging data suggest that EZH2 is a key regulator of this epigenetic rewiring. Several mechanisms drive AR-dependent castration resistance, notably AR splice variant expression, expression of the adrenalpermissive 3bHSD1 allele, and glucocorticoid receptor expression. Aberrant epigenetic regulation also promotes radioresistance by altering the expression of DNA repair- and cell cycle-related genes. Novel therapies are currently being developed to target these diverse genetic, epigenetic, and hormonal mechanisms promoting lineage plasticity-driven NEPC. [ABSTRACT FROM AUTHOR]

Background: Globally, despite prostate cancer (PCa) representing second most prevalent malignancy in male, the precise molecular mechanisms implicated in its pathogenesis remain unclear. Consequently, elucidating the key molecular regulators that govern disease progression could substantially contribute to the establishment of novel therapeutic strategies, ultimately advancing the management of PCa. Methods: A total of 49 PCa tissues and 43 adjacent normal tissues were collected from January 2017 to December 2021 at Zhongnan Hospital of Wuhan University. The advanced transcriptomic methodologies were employed to identify differentially expressed mRNAs in PCa. The expression of aspartoacylase (ASPA) in PCa was thoroughly evaluated using quantitative real-time PCR and Western blotting techniques. To elucidate the inhibitory role of ASPA in PCa cell proliferation and metastasis, a comprehensive set of in vitro and in vivo assays were conducted, including orthotopic and tumor-bearing mouse models (n = 8 for each group). A combination of experimental approaches, such as Western blotting, luciferase assays, immunoprecipitation assays, mass spectrometry, glutathione S-transferase pull-down experiments, and rescue studies, were employed to investigate the underlying molecular mechanisms of ASPA's action in PCa. The Student's t-test was employed to assess the statistical significance between two distinct groups, while one-way analysis of variance was utilized for comparisons involving more than two groups. A two-sided P value of less than 0.05 was deemed to indicate statistical significance. Results: ASPA was identified as a novel inhibitor of PCa progression. The expression of ASPA was found to be significantly down-regulated in PCa tissue samples, and its decreased expression was independently associated with patients' prognosis (HR = 0.60, 95% CI 0.40–0.92, P = 0.018). Our experiments demonstrated that modulation of ASPA activity, either through gain- or loss-of-function, led to the suppression or enhancement of PCa cell proliferation, migration, and invasion, respectively. The inhibitory role of ASPA in PCa was further confirmed using orthotopic and tumor-bearing mouse models. Mechanistically, ASPA was shown to directly interact with the LYN and inhibit the phosphorylation of LYN as well as its downstream targets, JNK1/2 and C-Jun, in both PCa cells and mouse models, in an enzyme-independent manner. Importantly, the inhibition of LYN activation by bafetinib abrogated the promoting effect of ASPA knockdown on PCa progression in both in vitro and in vivo models. Moreover, we observed an inverse relationship between ASPA expression and LYN activity in clinical PCa samples, suggesting a potential regulatory role of ASPA in modulating LYN signaling. Conclusion: Our findings provide novel insights into the tumor-suppressive function of ASPA in PCa and highlight its potential as a prognostic biomarker and therapeutic target for the management of this malignancy. [ABSTRACT FROM AUTHOR]

Purpose: Prostate cancer is the second most common cancer diagnosed worldwide and the third most common cancer among men in India. This study's objective was to characterise the mutational landscape of Indian prostate cancer using whole-exome sequencing to identify population-specific polymorphisms. Methods: Whole-exome sequencing was performed of 58 treatment-naive primary prostate tumors of Indian origin. Multiple computational and statistical analyses were used to profile the known common mutations, other deleterious mutations, driver genes, prognostic biomarkers, and gene signatures unique to each clinical parameter. Cox analysis was performed to validate survival-associated genes. McNemar test identified genes significant to recurrence and receiver-operating characteristic (ROC) analysis was conducted to determine its accuracy. OncodriveCLUSTL algorithm was used to deduce driver genes. The druggable target identified was modeled with its known inhibitor using Autodock. Results: TP53 was the most commonly mutated gene in our cohort. Three novel deleterious variants unique to the Indian prostate cancer subtype were identified: POLQ, FTHL17, and OR8G1. COX regression analysis identified ACSM5, a mitochondrial gene responsible for survival. CYLC1 gene, which encodes for sperm head cytoskeletal protein, was identified as an unfavorable prognostic biomarker indicative of recurrence. The novel POLQ mutant, also identified as a driver gene, was evaluated as the druggable target in this study. POLQ, a DNA repair enzyme implicated in various cancer types, is overexpressed and is associated with a poor prognosis. The mutant POLQ was subjected to structural analysis and modeled with its known inhibitor novobiocin resulting in decreased binding efficiency necessitating the development of a better drug. Conclusion: In this pilot study, the molecular profiling using multiple computational and statistical analyses revealed distinct polymorphisms in the Indian prostate cancer cohort. The mutational signatures identified provide a valuable resource for prognostic stratification and targeted treatment strategies for Indian prostate cancer patients. The DNA repair enzyme, POLQ, was identified as the druggable target in this study. [ABSTRACT FROM AUTHOR]

The androgen/androgen receptor (AR) axis represents a key driver of treatment resistance in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT) and targeted agents, and a deeper comprehension of resistance mechanisms is fundamental to adopt effective therapeutic strategies. We review the mechanisms of primary or secondary resistance to hormone therapy (HT) in PCa, especially focusing on available data and emerging evidence. First- and second-generation HT resistance has been associated with several AR-dependent and AR-independent mechanisms, ranging from the amplification of the AR gene locus to somatic AR mutations and the intratumoral synthesis of androgens from adrenal steroids and cholesterol. As reported in the current review, the development of novel and effective treatments is needed to personalize anticancer therapies in this setting and to finally improve clinical outcomes in patients with HT-resistant disease. [ABSTRACT FROM AUTHOR]

Androgen receptor (AR) signaling have been frequently targeted for treating prostate cancer (PCa). Even though primarily patients receive a good therapeutic outcome by targeting AR signaling axis, eventually it emerges resistance by altering the genetic makeup of prostate cells. However, to develop an effective therapeutic regime, it is essential to recognize key genetic alterations in PCa. The most common genetic alterations that give rise to distinct androgen different differentiation states are gene fusion of TMPRSS2 with ETS family genes, deletion, or mutation of tumor suppressor PTEN and TP53 gene, amplification or splicing of AR, altered DNA repair genes. In this review, we describe key genes and genetic changes that have been recognized to contribute to altered prostate environment. [ABSTRACT FROM AUTHOR]

Background: Metastasis is a crucial aspect of disease progression leading to death in patients with prostate cancer (PCa). However, its mechanism remains unclear. We aimed to explore the mechanism of lymph node metastasis (LNM) by analyzing the heterogeneity of tumor microenvironment (TME) in PCa using scRNA-seq. Methods: A total of 32,766 cells were obtained from four PCa tissue samples for scRNA-seq, annotated, and grouped. InferCNV, GSVA, DEG functional enrichment analysis, trajectory analysis, intercellular network evaluation, and transcription factor analysis were carried out for each cell subgroup. Furthermore, validation experiments targeting luminal cell subgroups and CXCR4 + fibroblast subgroup were performed. Results: The results showed that only EEF2 + and FOLH1 + luminal subgroups were present in LNM, and they appeared at the initial stage of luminal cell differentiation, which were comfirmed by verification experiments. The MYC pathway was enriched in the EEF2 + and FOLH1 + luminal subgroups, and MYC was associated with PCa LNM. Moreover, MYC did not only promote the progression of PCa, but also led to immunosuppression in TME by regulating PDL1 and CD47. The proportion of CD8 + T cells in TME and among NK cells and monocytes was lower in LNM than in the primary lesion, while the opposite was true for Th and Treg cells. Furthermore, these immune cells in TME underwent transcriptional reprogramming, including CD8 + T subgroups of CCR7 + and IL7R+, as well as M2-like monocyte subgroups expressing tumor-associated signature genes, like CCR7, SGKI, and RPL31. Furthermore, STEAP4+, ADGRF5 + and CXCR4+, and SRGNC + fibroblast subgroups were closely related to tumor progression, tumor metabolism, and immunosuppression, indicating their contributions in PCa metastasis. Meanwhile, The presence of CXCR4 + Fibroblasts in PCa was confirmed by polychromatic immunofluorescence. Conclusions: The significant heterogeneity of luminal, immune, and interstitial cells in PCa LNM may not only directly contribute to tumor progression, but also indirectly result in TME immunosuppression, which may be the cause of metastasis in PCa and in which MYC played an role. [ABSTRACT FROM AUTHOR]

Despite decades of research and clinical trials, metastatic castration-resistant prostate cancer (mCRPC) remains incurable and typically fatal. Current treatments may provide modest increases in progression-free survival but can come with significant adverse effects and are disaggregated from the diagnostic imaging needed to fully assess the spread of metastatic disease. A theranostic approach, using radiolabeled ligands that target the cell surface protein PSMA, simplifies the visualization and disease treatment process by enabling both to use similar agents. Here, we describe an exemplary case wherein a gentleman in his 70s with mCRPC on diagnosis was treated with 177Lu-PSMA-617 and abiraterone, and remains disease-free to date, over five years later. [ABSTRACT FROM AUTHOR]

Background/Aim: The purpose of this article was to review the association between the ETS-related gene (ERG) and the phosphatase and tensin homolog (PTEN) genes with pathologic parameters of prostate cancer, emphasizing on Gleason score. Materials and Methods: We performed a PubMed-based search of the literature emphasizing on articles that use pathological techniques, and especially on those that report the use immunohistochemical staining and FISH to investigate the association between ERG and PTEN mutations with the histopathologic parameters of prostate cancer. Results: ERG expression is frequently marked in patients with prostate cancer, usually due to the occurrence of the TMPRSS2:ERG gene fusion. Although some studies reported a potential link between the expression of ERG and Gleason score, there is no strong evidence supporting this finding. On the contrary, there is more solid evidence correlating loss of PTEN expression with worse prognosis and higher Gleason scores. Few studies correlate the over-expression of ERG gene with the loss of PTEN expression. Finally, PTEN and ERG have been studied as potential therapeutic targets, and several promising results have been reported. Conclusion: Although, at some degree, ERG expression seems to be associated with the morphological features of prostate cancer, different studies reported controversial results. However, expression of PTEN is more clearly associated with the pathology and clinical course of the disease. More research is required to elucidate the role of these molecules in the molecular pathology of prostate cancer, as well as their potential use as therapeutic targets. [ABSTRACT FROM AUTHOR]

A review of the current treatment options for prostate cancer and the formation of resistance to these regimens has been compiled including primary, acquired, and cross‐resistance. The diversification of the pathways involved and the escape routes the tumor is utilizing have been addressed. Whereas early stages of tumor can be cured, there is no treatment available after a point of no return has been reached, leaving palliative treatment as the only option. The major reasons for this outcome are the heterogeneity of tumors, both inter‐ and intra‐individually and the nearly endless number of escape routes, which the tumor can select to overcome the effects of treatment. This means that more focus should be applied to the individualization of both diagnosis and therapy of prostate cancer. In addition to current treatment options, novel drugs and ongoing clinical trials have been addressed in this review. [ABSTRACT FROM AUTHOR]

While screening and early detection have reduced mortality from prostate cancer, castration-resistant disease (CRPC) is still incurable. Here, we report that combined EZH2/HDAC inhibitors potently kill CRPCs and cause dramatic tumor regression in aggressive human and mouse CRPC models. Notably, EZH2 and HDAC both transmit transcriptional repressive signals: regulating histone H3 methylation and histone deacetylation, respectively. Accordingly, we show that suppression of both EZH2 and HDAC are required to derepress/induce a subset of EZH2 targets, by promoting the sequential demethylation and acetylation of histone H3. Moreover, we find that the induction of one of these targets, ATF3, which is a broad stress response gene, is critical for the therapeutic response. Importantly, in human tumors, low ATF3 levels are associated with decreased survival. Moreover, EZH2- and ATF3-mediated transcriptional programs inversely correlate and are most highly/lowly expressed in advanced disease. Together, these studies identify a promising therapeutic strategy for CRPC and suggest that these two major epigenetic regulators buffer prostate cancers from a lethal response to cellular stresses, thereby conferring a tractable therapeutic vulnerability. Epigenetic, transcriptional, and functional studies show that two major epigenetic regulators (EZH2 and HDAC) buffer advanced prostate cancer from lethal stress responses, revealing a promising combination therapy for castration-resistant disease. [ABSTRACT FROM AUTHOR]