Therapeutic Strategy For Prostate Cancer Research Articles

Celastrol attenuates the invasion and migration and augments the anticancer effects of olaparib in prostate cancer

BackgroundProstate cancer (PCa) is a leading malignancy among men globally, with rising incidence rates emphasizing the critical need for better detection and therapeutic approaches. The roles of HSP90AB1 and PARP1 in prostate cancer cells suggest potential targets for enhancing treatment efficacy.MethodsThis study investigated the overexpression of HSP90AB1 and PARP1 in prostate cancer cells and the impact of HSP90AB1 knockdown on the sensitivity of these cells to the PARP inhibitor olaparib. We also explored the combined effect of olaparib and celastrol, an HSP90 inhibitor, on the clonogenic survival, migration, proliferation, and overall viability of prostate cancer cells, alongside the modulation of the PI3K/AKT pathway. An in vivo PC3 xenograft mouse model was used to assess the antitumor effects of the combined treatment.ResultsOur findings revealed significant overexpression of HSP90AB1 and PARP1 in prostate cancer cells. Knockdown of HSP90AB1 increased cell sensitivity to olaparib. The combination of olaparib and celastrol significantly reduced prostate cancer cell survival, migration, proliferation, and enhanced cumulative DNA damage. Celastrol also downregulated the PI3K/AKT pathway, increasing cell susceptibility to olaparib. In vivo experiments demonstrated that celastrol and olaparib together exerted strong antitumor effects.ConclusionsThe study indicates that targeting both HSP90AB1 and PARP1 presents a promising therapeutic strategy for prostate cancer. The synergistic combination of celastrol and olaparib enhances the efficacy of treatment against prostate cancer, offering a potent approach to combat this disease.

Liquiritigenin inhibits the migration, invasion, and EMT of prostate cancer through activating ER stress

Liquiritigenin (LQ) is a monomeric compound found in licorice, a leguminous plant, and has been reported to exhibit antitumor effects in various lines of cancer cells. However, the underlying molecular mechanisms by which LQ exerts its antitumor effects remain largely unknown. In this study, the effects of LQ on the migration, invasion, and epithelial-mesenchymal transition (EMT) of prostate cancer (PCa) cells were investigated. We found that LQ effectively inhibited the migration and invasion of PCa cells in vitro, and this effect was further confirmed in xenograft lung metastasis models. In addition, LQ was found to activate endoplasmic reticulum stress (ER stress) in PCa cells. Further studies found that LQ upregulated the expression of inositol-requiring enzyme type 1α (IRE1). When IRE1 was knocked down, we observed a weakened inhibitory effect of LQ treatment on the migration and invasion of PCa cells. This observation suggests that LQ may inhibit the migration, invasion and EMT of PCa cells through activating the IRE1 branch of ER stress. In conclusion, our research may provide a novel therapeutic strategy for PCa.

Germline mutations of TP53 gene can be a key factor in prostate cancer genesis

Aim: The aim of this study is to investigate whether germline alterations of exon 5 of TP53 gene could be detected in the blood of known men with prostate cancer and to assess the potential association between the genomic alteration affecting this gene and clinicopathological characteristics of the patients. Methods: Forty-eight blood samples from men diagnosed with prostate cancer were analyzed for TP53 germline mutations and confirmed by Sanger sequencing. The frequency and distribution of high-frequency mutations were analyzed according to the pathological criteria of the patients and a computational study was performed to assess the effect of new mutations. Results: The Sanger sequencing revealed that 79% of the population studied carry mutations in TP53 gene. In summary, a total of 137 mutations have been identified in this gene, out of which 115 are new mutations. Frameshift mutations were the most frequent; the mutation c.392delA was recorded in fifteen cases (31%); the mutations c.383delC and c.432delG were observed at a frequency of 12.5% and 10% respectively. The most frequent missense mutation was the variant c.502C>A (p.His168Asn) identified in eleven patients (23%). One nonsense mutation was identified in one patient and resulted in a stop codon in position 126 (tyrosine). All codons affected by these alterations are part of the DNA binding domain of the protein TP53. Conclusions: The germline mutation frequency observed in prostate cancer patients, and the new mutations recorded in TP53 gene, could be in favor of a potential association of genomic alterations in this gene and prostate cancer genesis, thereby constituting a tool, similar to other genes in the DNA repair pathway such as BRCA1 and BRCA2. This could contribute to the advancement of diagnosis and therapeutic strategies for prostate cancer.

Index tumor location affected early biochemical recurrence after radical prostatectomy in patients with negative surgical margin: a retrospective study

BackgroundIndex tumors are the most aggressive tumors of the prostate. However, their clinical significance remains unclear. This study aimed to assess the incidence of index tumor location according to the zonal origin and whether these locations affect the prognosis after radical prostatectomy in patients with negative surgical margins.MethodsThis single-centered, retrospective study evaluated 1,109 consecutive patients who underwent radical prostatectomies. An index tumor was defined as the largest tumor in the prostate gland. We detected these locations based on McNeal's zonal origin using whole-mount sections. Biochemical recurrence (BCR) free survival curves were generated using the Kaplan–Meier method. Univariate and multivariate analyses using the Cox proportional hazards model were performed to determine the predictive factors for early BCR (within 1-year).ResultsA total of 621 patients with negative surgical margins who did not receive adjuvant therapy were included in this study. The index tumor were located in the transitional zone in 191 patients (30.8%), the peripheral zone in 399 patients (64.3%), and the central zone in 31 patients (5.0%). In total, 22 of 621 patients (3.5%) experienced early BCR and 70 patients (11.2%) experienced overall BCR at a median follow-up of 61.7 months. According to the index tumor location, the early BCR-free rates were 99.5%, 95.7 %, and 83.3% in the transitional, peripheral, and central zones, respectively. On multivariate analysis, the index tumor in the central zone was an independent predictor of early BCR with negative surgical margins following radical prostatectomy, followed by prostatectomy pathological grade, index tumor in the peripheral zone, and high prostate-specific antigen level.ConclusionsWe assessed the significance of index tumor location in patients with negative surgical margins following radical prostatectomy. Index tumors located in the central zone, although infrequent, were the strongest predictive factors for early BCR. Our results may allow urologists and patients to reconsider the therapeutic strategies for prostate cancer.

The Impact of High Intensity Focused Ultrasound (HIFU) on Tumor-Specific Immune Responses of Prostate Cancer.

High intensity focused ultrasound (HIFU), also referred to as focused ultrasound surgery (FUS), has garnered recent attention as a non-invasive therapeutic strategy for prostate cancer. It utilizes focused acoustic energy to achieve localized thermal ablation, while also potentially exerting immunomodulatory effects. This review aims to elucidate the mechanisms underlying how HIFU influences tumor-specific immune responses in prostate cancer. These mechanisms include the release of tumor-associated antigens and damage-associated molecular patterns, the activation of innate immune cells, the facilitation of antigen presentation to adaptive immune cells, the enhancement of activation and proliferation of tumor-specific cytotoxic T lymphocytes, and the attenuation of the immunosuppressive tumor microenvironment by reducing the activity of regulatory T cells and myeloid-derived suppressor cells. Both preclinical investigations and emerging clinical data in prostate cancer models highlight HIFU's potential to modulate the immune system, as evidenced by increased infiltration of effector immune cells, elevated levels of pro-inflammatory cytokines, and improved responsiveness to immune checkpoint inhibitors. HIFU induces immunogenic cell death, leading to the release of tumor antigens and danger signals that activate dendritic cells and facilitate cross-presentation to cytotoxic T cells. Additionally, FUS ablation reduces immunosuppressive cells and increases infiltration of CD8+ T cells into the tumor, reshaping the tumor microenvironment. By priming the immune system while overcoming immunosuppression, combining FUS with other immunotherapies like checkpoint inhibitors and cancer vaccines holds promise for synergistic anti-tumor effects. Despite challenges in optimizing parameters and identifying suitable patients, FUS represents a novel frontier by modulating the tumor microenvironment and enhancing anti-tumor immunity through a non-invasive approach.

Metabolic characterization of sphere-derived prostate cancer stem cells reveals aberrant urea cycle in stemness maintenance.

Alteration of cell metabolism is one of the essential characteristics of tumor growth. Cancer stem cells (CSCs) are the initiating cells of tumorigenesis, proliferation, recurrence, and other processes, and play an important role in therapeutic resistance and metastasis. Thus, identification of the metabolic profiles in prostate cancer stem cells (PCSCs) is critical to understanding prostate cancer progression. Using untargeted metabolomics and lipidomics methods, we show distinct metabolic differences between prostate cancer cells and PCSCs. Urea cycle is the most significantly altered metabolic pathway in PCSCs, the key metabolites arginine and proline are evidently elevated. Proline promotes cancer stem-like characteristics via the JAK2/STAT3 signaling pathway. Meanwhile, the enzyme pyrroline-5-carboxylate reductase 1 (PYCR1), which catalyzes the conversion of pyrroline-5-carboxylic acid to proline, is highly expressed in PCSCs, and the inhibition of PYCR1 suppresses the stem-like characteristics of prostate cancer cells and tumor growth. In addition, carnitine and free fatty acid levels are significantly increased, indicating reprogramming of fatty acid metabolism in PCSCs. Reduced sphingolipid levels and increased triglyceride levels are also observed. Collectively, our data illustrate the comprehensive landscape of the metabolic reprogramming of PCSCs and provide potential therapeutic strategies for prostate cancer.

Three-Dimensional Genomics: A New Perspective and Therapeutic Strategies in Prostate Cancer Research

Prostate cancer (PC) poses significant health risks to men globally. Enhancing our understanding of prostate cancer biology is crucial for facilitating early diagnosis and effective treatment strategies. A multitude of high-throughput sequencing studies, encompassing whole genome resequencing, transcriptome sequencing, and genome-wide association studies, have unearthed vital point mutations, structural variations, and epigenomic alterations linked to prostate cancer. These findings have significantly enriched our knowledge of the genomic framework for prostate cancer. Still, these investigations have predominantly centered on the one- or two-dimensional landscape of the genome. Research in three-dimensional genomics underscores the critical role of the genome's three-dimensional spatial structure in maintaining normal cellular functions. Additionally, it demonstrates that dysregulation of key genes in numerous cancers relates to the chromatin's spatial organization across various levels. This article explores the intricate three-dimensional architecture of chromosomes. It outlines the progressive development of techniques used in three-dimensional genomic research and synthesizes the application of these techniques in the study of prostate cancer biology. Furthermore, it proposes potential therapeutic strategies for prostate cancer.

Abstract 5420: NLRX1 involves in prostate cancer cell growth, survival and migration

Abstract Prostate cancer (PCa) is one of the most common male cancer and is the second leading cause of death in men. The basic working components about its cause and progression are not surely known in the research as well as the practitioner community. The current curing therapies such as surgery, radiation therapy, cryotherapy, and hormone therapy are not very encouraging. Subsequently, there is a need to investigate new potential targets for focused treatment. NLRX1 (NOD9 or NLR family member X1) is one member among the NLRs and is a non-inflammasome forming NLR sub-group localized in mitochondria. Previous studies showed that NLRX1 is involved as a tumor suppressor in colorectal cancer and hepatocellular carcinoma. However, NLRX1 serves as tumor promoter in breast cancer and head and neck cancer sarcoma. The present study focuses on the role of NLRX1 in prostate cancer cells under stress conditions including serum-free and hydrogen peroxide (H2O2) to understand cell regulation and functions of NLRX1. We used human prostate cancer PC3 and LNCaP cell lines as the models and the following methods, including Annexin V/PI staining for cell viability, BrdU incorporation for cell proliferation, mitoSOX staining for mitochondrial ROS, wound healing assay for cell migration and Boyden chamber for cell invasion. First, we assessed the TCGA database via UCSC Xena and found that prostate cancer tumors have high NLRX1 expression than normal tissues. Next, we knock down the NLRX1 through lentivirus transduction. We found that silencing NLRX1 expression can decrease cell proliferation in PC3 cells. Furthermore, silencing NLRX1 can significantly decrease cell viability under H2O2 in PC3 cells and serum-free condition in both cancer cell lines. In addition, we found that H2O2-induced cell death is reversed by necroptosis inhibitor Nec-1. Moreover, NLRX1 silencing reduces cell migration in both PC3 and LNCaP cells and can inhibit cell invasion in both cell lines at 24 h. These results suggest that NLRX1 is a positive regulator of cell growth, migration and invasion in prostate cancer cells, and NLRX1 provides a cell-protective role in response to H2O2 and serum-free stress. Thus, this study will provide a potential target for the development of a therapeutic strategy for prostate cancer. Citation Format: Wan-Wan Lin, Varsha Rathore. NLRX1 involves in prostate cancer cell growth, survival and migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5420.

8-Br-cGMP activates HSPB6 and increases the antineoplastic activity of quinidine in prostate cancer.

Heat shock protein family B [small] member 6 (HSPB6), widely found in various muscles, has been recently identified as a tumor suppressor gene. However, its role in prostate cancer remains unexplored. Herein, we investigated the expression of HSPB6 in prostate cancer and its association with prognosis. Our findings revealed that HSPB6 downregulation in prostate cancer correlated with a poor prognosis. Moreover, we discovered that HSPB6 can be phosphorylated and activated by 8-Br-cGMP, leading to apoptosis in prostate cancer cells by activating Cofilin. Additionally, we demonstrated that knocking down E2F1 by quinidine administration enhances the transcriptional level of HSPB6. Furthermore, we evaluated the combination of quinidine and 8-Br-cGMP as a potential therapeutic strategy for prostate cancer. Our results revealed that the combined treatment was more effective than either treatment alone in inhibiting the growth of prostate cancer through the HSPB6 pathway, both in vitro and in vivo. Overall, our study provides compelling evidence that HSPB6 suppresses malignant behavior in prostate cancer by inducing apoptosis. The combination of quinidine and 8-Br-cGMP emerges as a promising approach for the treatment of prostate cancer.

Dysregulation of RNA-Exosome machinery is directly linked to major cancer hallmarks in prostate cancer: Oncogenic role of PABPN1

Novel biomarkers and therapeutic strategies for prostate-cancer (PCa) are required to overcome its lethal progression. The dysregulation/implication of the RNA-Exosome-complex (REC; cellular machinery controlling the 3′-5′processing/degradation of most RNAs) in different cancer-types, including PCa, is poorly known. Herein, different cellular/molecular/preclinical approaches with human PCa-samples (tissues and/or plasma of 7 independent cohorts), and in-vitro/in-vivo PCa-models were used to comprehensively characterize the REC-profile and explore its role in PCa. Moreover, isoginkgetin (REC-inhibitor) effects were evaluated on PCa-cells. We demonstrated a specific dysregulation of the REC-components in PCa-tissues, identifying the Poly(A)-Binding-Protein-Nuclear 1 (PABPN1) factor as a critical regulator of major cancer hallmarks. PABPN1 is consistently overexpressed in different human PCa-cohorts and associated with poor-progression, invasion and metastasis. PABPN1 silencing decreased relevant cancer hallmarks in multiple PCa-models (proliferation/migration/tumourspheres/colonies, etc.) through the modulation of key cancer-related lncRNAs (PCA3/FALEC/DLEU2) and mRNAs (CDK2/CDK6/CDKN1A). Plasma PABPN1 levels were altered in patients with metastatic and tumour-relapse. Finally, pharmacological inhibition of REC-activity drastically inhibited PCa-cell aggressiveness. Altogether, the REC is drastically dysregulated in PCa, wherein this novel molecular event/mechanism, especially PABPN1 alteration, may be potentially exploited as a novel prognostic and therapeutic tool for PCa.

Nucleophosmin 1 cooperates with BRD4 to facilitate c-Myc transcription to promote prostate cancer progression

Nucleophosmin 1 (NPM1) is a multifunctional protein that promotes tumor progression in various cancers and is associated with a poor prognosis of prostate cancer (PCa). However, the mechanism by which NPM1 exerts its malignant potential in PCa remains elusive. Here, we showed that NPM1 is overexpressed in PCa cell lines and tissues and that the dysregulation of NPM1 promotes PCa proliferation. We also demonstrated that NPM1 transcriptionally upregulates c-Myc expression in PCa cells that is diminished by blockade of bromodomain-containing protein 4 (BRD4). Furthermore, we detected a correlation between NPM1 and c-Myc in patient PCa specimens. Mechanistically, NPM1 influences and cooperates with BRD4 to facilitate c-Myc transcription to promote PCa progression. In addition, JQ1, a bromodomain and extra-terminal domain (BET) inhibitor, in combination with NPM1 inhibition suppresses PCa progression in vitro and in vivo. These results indicate that NPM1 promotes PCa progression through a c-Myc -mediated pathway via BRD4, and blockade of the NPM1–c-Myc oncogenic pathway may be a therapeutic strategy for PCa.

Making the Case for Autophagy Inhibition as a Therapeutic Strategy in Combination with Androgen-Targeted Therapies in Prostate Cancer.

Androgen receptor targeting remains the primary therapeutic strategy in prostate cancer, encompassing androgen biosynthesis inhibitors and androgen receptor antagonists. While both androgen-receptor-positive and "castration-resistant" prostate cancer are responsive to these approaches, the development of resistance is an almost inevitable outcome leading to the castration-resistant form of the disease. Given that "cytoprotective" autophagy is considered to be a predominant mechanism of resistance to various chemotherapeutic agents as well as to radiation in the cancer literature, the purpose of this review is to evaluate whether autophagy plays a central role in limiting the utility of androgen deprivation therapies in prostate cancer. Unlike most of our previous reports, where multiple functional forms of autophagy were identified, making it difficult if not impossible to propose autophagy inhibition as a therapeutic strategy, the cytoprotective form of autophagy appears to predominate in the case of androgen deprivation therapies. This opens a potential pathway for improving the outcomes for prostate cancer patients once effective and reliable pharmacological autophagy inhibitors have been developed.

Long-term Prostate Cancer–specific Mortality After Prostatectomy, Brachytherapy, External Beam Radiation Therapy, Hormonal Therapy, or Monitoring for Localized Prostate Cancer

BackgroundThe optimal treatment of localized prostate cancer (PCa) remains controversial. ObjectiveTo compare long-term survival among men who underwent radical prostatectomy (RP), brachytherapy (BT), external beam radiation therapy (EBRT), primary androgen deprivation therapy (PADT), or monitoring (active surveillance [AS]/watchful waiting [WW]) for PCa. Design, setting, and participantsThis is a cohort study with long-term follow-up from the multicenter, prospective, largely community-based Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. Men with biopsy-proven, clinical T1–3aN0M0, localized PCa were consecutively accrued within 6 mo of diagnosis and had clinical risk data and at least 12 mo of follow-up after diagnosis available. Outcome measurements and statistical analysisPCa risk was assessed, and multivariable analyses were performed to compare PCa-specific mortality (PCSM) and all-cause mortality by primary treatment, with extensive adjustment for age and case mix using the Cancer of the Prostate Risk Assessment (CAPRA) score and a well-validated nomogram. Results and limitationsAmong 11 864 men, 6227 (53%) underwent RP, 1645 (14%) received BT, 1462 (12%) received EBRT, 1510 (13%) received PADT, and 1020 (9%) were managed with AS/WW. At a median of 9.4 yr (interquartile range 5.8–13.7) after treatment, 764 men had died from PCa. After adjusting for CAPRA score, the hazard ratios for PCSM with RP as the reference were 1.57 (95% confidence interval [CI] 1.24–1.98; p < 0.001) for BT, 1.55 (95% CI 1.26–1.91; p < 0.001) for EBRT, 2.36 (95% CI 1.94–2.87; p < 0.001) for PADT, and 1.76 (95% CI 1.30–2.40; p < 0.001) for AS/WW. In models for long-term outcomes, PCSM differences were negligible for low-risk disease and increased progressively with risk. Limitations include the evolution of diagnostic and therapeutic strategies for PCa over time. In this nonrandomized study, the possibility of residual confounding remains salient. ConclusionsIn a large, prospective cohort of men with localized PCa, after adjustment for age and comorbidity, PCSM was lower after local therapy for those with higher-risk disease, and in particular after RP. Confirmation of these results via long-term follow-up of ongoing trials is awaited. Patient summaryWe evaluated different treatment options for localized prostate cancer in a large group of patients who were treated mostly in nonacademic medical centers. Results from nonrandomized trials should be interpret with caution, but even after careful risk adjustment, survival rates for men with higher-risk cancer appeared to be highest for patients whose first treatment was surgery rather than radiotherapy, hormones, or monitoring.

The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer Growth.

Bromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of several genes including protooncogene cellular myelocytomatosis (c-Myc). c-Myc is difficult to target directly by agents due to its disordered alpha helical protein structure and predominant nuclear localization. The epigenetic targeting of c-Myc by BD inhibitors is an attractive therapeutic strategy for prostate cancer (PC) associated with increased c-Myc upregulation with advancing disease. MT-1 is a bivalent BD inhibitor that is 100-fold more potent than the first-in-class BD inhibitor JQ1. MT-1 decreased cell viability and causes cell cycle arrest in G0/G1 phase in castration-sensitive and resistant PC cell lines in a dose-dependent fashion. The inhibition of c-Myc function by MT-1 was molecularly corroborated by the de-repression of Protein Kinase D1 (PrKD) and increased phosphorylation of PrKD substrate proteins: threonine 120, serine 11, and serine 216 amino acid residues in β-Catenin, snail, and cell division cycle 25c (CDC25c) proteins, respectively. The treatment of 3D cell cultures derived from three unique clinically annotated heavily pretreated patient-derived PC xenografts (PDX) mice models with increasing doses of MT-1 demonstrated the lowest IC50 in tumors with c-Myc amplification and clinically resistant to Docetaxel, Cabazitaxel, Abiraterone, and Enzalutamide. An intraperitoneal injection of either MT-1 or in combination with 3jc48-3, an inhibitor of obligate heterodimerization with MYC-associated protein X (MAX), in mice implanted with orthotopic PC PDX, decreased tumor growth. This is the first pre-clinical study demonstrating potential utility of MT-1 in the treatment of PC with c-Myc dysregulation.

Nanoparticle-Based Radioconjugates for Targeted Imaging and Therapy of Prostate Cancer.

Prostate cancer is the second most frequent malignancy in men worldwide and the fifth leading cause of death by cancer. Although most patients initially benefit from therapy, many of them will progress to metastatic castration-resistant prostate cancer, which still remains incurable. The significant mortality and morbidity rate associated with the progression of the disease results mainly from a lack of specific and sensitive prostate cancer screening systems, identification of the disease at mature stages, and failure of anticancer therapy. To overcome the limitations of conventional imaging and therapeutic strategies for prostate cancer, various types of nanoparticles have been designed and synthesized to selectively target prostate cancer cells without causing toxic side effects to healthy organs. The purpose of this review is to briefly discuss the selection criteria of suitable nanoparticles, ligands, radionuclides, and radiolabelling strategies for the development of nanoparticle-based radioconjugates for targeted imaging and therapy of prostate cancer and to evaluate progress in the field, focusing attention on their design, specificity, and potential for detection and/or therapy.

Cancer-Associated Fibroblast: Role in Prostate Cancer Progression to Metastatic Disease and Therapeutic Resistance

Prostate cancer (PCa) is one of the most common cancers in European males. Although therapeutic approaches have changed in recent years, and several new drugs have been approved by the Food and Drug Administration (FDA), androgen deprivation therapy (ADT) remains the standard of care. Currently, PCa represents a clinical and economic burden due to the development of resistance to ADT, paving the way to cancer progression, metastasis, and to long-term side effects induced by ADT and radio-chemotherapeutic regimens. In light of this, a growing number of studies are focusing on the tumor microenvironment (TME) because of its role in supporting tumor growth. Cancer-associated fibroblasts (CAFs) have a central function in the TME because they communicate with prostate cancer cells, altering their metabolism and sensitivity to drugs; hence, targeted therapy against the TME, and, in particular, CAFs, could represent an alternative therapeutic approach to defeat therapy resistance in PCa. In this review, we focus on different CAF origins, subsets, and functions to highlight their potential in future therapeutic strategies for prostate cancer.

WIN Symposium 2022 - Abstract Poster Presentations.

WIN Symposium 2022 - Abstract Poster Presentations.

The FOXP4-AS1/miR-3130-3p/SP4 feedback loop is associated with prostate cancer.

The vital function of mounting long noncoding RNAs (lncRNAs) in prostate cancer (PCa) has been illustrated in increasing reports. However, the roles of many lncRNAs in PCa have not been deciphered. A total of 62 pairs of PCa and adjacent normal tissue samples were provided by PCa patients undergoing surgery. Extensive assays were conducted in this study to investigate the role of FOXP4 antisense RNA 1 (FOXP4-AS1) in PCa tumorigenesis. This study elucidated that FOXP4-AS1 expression was elevated in PCa tissue samples and cell lines. Loss-of-function experiments revealed that depleted FOXP4-AS1 inhibited PCa cell proliferation in vitro and retarded tumor growth in vivo. Mechanically, FOXP4-AS1 functioned as a competing endogenous RNA (ceRNA) of miR-3130-3p, releasing SP4 from the inhibitory effect of miR-3130-3p. Rescue assays validated that FOXP4-AS1 modulated PCa progression via SP4. Interestingly, SP4 is known as a transcription factor and was predicted to bind with the promoter region of FOXP4-AS1. This current research confirmed that SP4 activated the transcription activity of FOXP4-AS1 and thus positively regulated its expression. To conclude, we discovered that FOXP4-AS1, miR-3130-3p, and SP4 constitute a feedback loop and contribute to PCa tumorigenesis, providing a new valuable diagnosis and therapeutic strategy for PCa.

To bind or not to bind: Cistromic reprogramming in prostate cancer.

The term “cistrome” refers to the genome-wide location of regulatory elements associated with transcription factor binding-sites. The cistrome of key regulatory factors in prostate cancer etiology are substantially reprogrammed and altered during prostatic transformation and disease progression. For instance, the cistrome of the androgen receptor (AR), a ligand-inducible transcription factor central in normal prostate epithelium biology, is directly impacted and substantially reprogrammed during malignant transformation. Accumulating evidence demonstrates that additional transcription factors that are frequently mutated, or aberrantly expressed in prostate cancer, such as the pioneer transcription factors Forkhead Box A1 (FOXA1), the homeobox protein HOXB13, and the GATA binding protein 2 (GATA2), and the ETS-related gene (ERG), and the MYC proto-oncogene, contribute to the reprogramming of the AR cistrome. In addition, recent findings have highlighted key roles for the SWI/SNF complex and the chromatin-modifying helicase CHD1 in remodeling the epigenome and altering the AR cistrome during disease progression. In this review, we will cover the role of cistromic reprogramming in prostate cancer initiation and progression. Specifically, we will discuss the impact of key prostate cancer regulators, as well as the role of epigenetic and chromatin regulators in relation to the AR cistrome and the transformation of normal prostate epithelium. Given the importance of chromatin-transcription factor dynamics in normal cellular differentiation and cancer, an in-depth assessment of the factors involved in producing these altered cistromes is of great relevance and provides insight into new therapeutic strategies for prostate cancer.

Dietary stilbenes as modulators of specific miRNAs in prostate cancer.

Accumulated experimental data have suggested that natural plant products may be effective miRNA-modulating chemopreventive and therapeutic agents. Dietary polyphenols such as flavonoids, stilbenes, and lignans, among others, have been intensively studied for their miRNA-mediated cardioprotective, antioxidant, anti-inflammatory and anticancer properties. The aim of this review is to outline known stilbene-regulated miRNAs in cancer, with a special focus on the interplay between various miRNAs and MTA1 signaling in prostate cancer. MTA1 is an epigenetic reader and an oncogenic transcription factor that is overexpressed in advanced prostate cancer and metastasis. Not surprisingly, miRNAs that are linked to MTA1 affect cancer progression and the metastatic potential of cells. Studies led to the identification of MTA1-associated pro-oncogenic miRNAs, which are regulated by stilbenes such as resveratrol and pterostilbene. Specifically, it has been shown that inhibition of the activity of the MTA1 regulated oncogenic miR-17 family of miRNAs, miR-22, and miR-34a by stilbenes leads to inhibition of prostatic hyperplasia and tumor progression in mice and reduction of proliferation, survival and invasion of prostate cancer cells in vitro. Taken together, these findings implicate the use of resveratrol and its analogs as an attractive miRNA-mediated chemopreventive and therapeutic strategy in prostate cancer and the use of circulating miRNAs as potential predictive biomarkers for clinical development.