Androgen Receptor Signaling Pathway Research Articles

ERG-Mediated Coregulator Complex Formation Maintains Androgen Receptor Signaling in Prostate Cancer.

The TMPRSS2-ERG fusion is the most common genomic rearrangement in human prostate cancer. However, in established adenocarcinoma, it is unknown how the ERG oncogene promotes a cancerous phenotype and maintains downstream androgen receptor (AR) signaling pathways. In this study, we utilized a murine prostate organoid system to explore the effects of ERG on tumorigenesis and determined the mechanism underlying prostate cancer dependence on ERG. Prostate organoids lacking PTEN and overexpressing ERG (Pten-/- R26-ERG) faithfully recapitulated distinct stages of prostate cancer disease progression. In this model, deletion of ERG significantly dampened AR-dependent gene expression. While ERG was able to reprogram the AR cistrome in the process of prostate carcinogenesis, ERG knockout in established prostate cancer organoids did not drastically alter AR binding, H3K27ac enhancer, or open chromatin profiles at these reprogrammed sites. Proteomic analysis of DNA-bound AR complexes demonstrated that ERG deletion causes a loss of recruitment of critical AR coregulators and basal transcriptional machinery, including NCOA3 and RNA polymerase II, but does not alter AR binding itself. Together, these data reveal a novel mechanism of ERG oncogene addiction in prostate cancer, whereby ERG facilitates AR signaling by maintaining coregulator complexes at AR bound sites across the genome. SIGNIFICANCE: These findings exploit murine organoid models to uncover the mechanism of ERG-mediated tumorigenesis and subsequent oncogenic dependencies in prostate cancer.

Endocrine-disrupting potential of polybrominated diphenyl ethers (PBDEs) on androgen receptor signaling: a structural insight

Polybrominated diphenyl ethers (PBDEs) are commonly used in array of consumer items to improve their fire-resisting ability. The PBDE compounds are non-covalently linked with substrate polymer matrices resulting in their consistent leach out and ubiquitous presence in the environment. Increasing evidence of PBDEs having endocrine-disrupting effects perturbing the homeostasis of sex hormones and causing adverse effects on reproductive system has been shown. The two frequently reported PBDE congeners from human samples are 2,2′,4,4′-tetra-bromodiphenyl ether (BDE-47) and 2,2′,4,4′,5-penta-bromodiphenyl ether (BDE-99). The focus of the present study was to investigate the potential disruptive action of BDE-47 and BDE-99 and their hydroxy (HO-) and methoxy (MeO-) structural analogues on androgen receptor (AR). The structural binding characterization of these ligands against AR was accomplished following the induced fit docking and binding energy estimations. The results revealed that the indicated compounds are packed tightly in the AR ligand-binding pocket, displaying similar binding pattern to the native-ligand testosterone. The MeO- structural analogues of both the PBDEs showed higher binding energy values than their HO- counterparts with 6-MeO-BDE-99 having binding energy values similar to testosterone and highest among all the ligands in this study. In conclusion, the results of this study suggested potential disruptive action of BDE-47 and BDE-99 and their analogues particularly for 6-MeO-BDE-99 on AR signaling pathway, which may adversely impact the male reproductive growth and function.

Comparison of Machine Learning Models for the Androgen Receptor.

The androgen receptor (AR) is a target of interest for endocrine disruption research, as altered signaling can affect normal reproductive and neurological development for generations. In an effort to prioritize compounds with alternative methodologies, the U.S. Environmental Protection Agency (EPA) used in vitro data from 11 assays to construct models of AR agonist and antagonist signaling pathways. While these EPA ToxCast AR models require in vitro data to assign a bioactivity score, Bayesian machine learning methods can be used for prospective prediction from molecule structure alone. This approach was applied to multiple types of data corresponding to the EPA's AR signaling pathway with proprietary software, Assay Central. The training performance of all machine learning models, including six other algorithms, was evaluated by internal 5-fold cross-validation statistics. Bayesian machine learning models were also evaluated with external predictions of reference chemicals to compare prediction accuracies to published results from the EPA. The machine learning model group selected for further studies of endocrine disruption consisted of continuous AC50 data from the February 2019 release of ToxCast/Tox21. These efforts demonstrate how machine learning can be used to predict AR-mediated bioactivity and can also be applied to other targets of endocrine disruption.

USP26 deubiquitinates androgen receptor (AR) in the maintenance of sperm maturation and spermatogenesis through the androgen receptor signaling pathway.

The post-translational modifications of proteins control various physiological and pathological events in cells. In this study, we investigated the influences of the X-linked deubiquitination enzyme USP26 in mediating androgen receptor (AR) deubiquitination in the physiological events of sperm maturation and spermatogenesis through the AR signaling pathway. The cell cycle results detected with flow cytometry (FCM) showed that both of the proteins, USP26 and AR, could facilitate the transition of G1-G2 phase in the Leydig cells (TM3). This effect also promoted the proliferation of the Leydig cells. The cell cycle studies performed using FCM detected that the 2 proteins, USP26 and AR, could facilitate the transition of G1-G2 phase in the Leydig cells (TM3). This effect also promoted the proliferation of the Leydig cells. Moreover, the results from co-immunoprecipitation (CO-IP), immunofluorescence and western blot assays showed that the physiological process due to USP26 interacted with AR and influenced AR deubiquitination, thus upregulating the proteins CCND1 and SPATA46 - which are associated with cell cycle progression and spermatogenesis - as well as decreasing the expression of TP73. Thus, these processes took place through the AR signaling pathway. Furthermore, the USP26 mimic plasmid transfection enhanced these activities, while, conversely, USP26 and AR inhibitor plasmid transfection suppressed the physiological events. Taken together, the effects of AR deubiquitinated by USP26 could modulate sperm maturation and spermatogenesis through the androgen receptor signaling pathway.

Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer.

The androgen receptor (AR) is the main therapeutic target in advanced prostate cancer, because it regulates the growth and progression of prostate cancer cells. Patients may undergo multiple lines of AR-directed treatments, including androgen-deprivation therapy, AR signaling inhibitors (abiraterone acetate, enzalutamide, apalutamide, or darolutamide), or combinations of these therapies. Yet, tumors inevitably develop resistance to the successive lines of treatment. The diverse mechanisms of resistance include reactivation of the AR and dysregulation of AR cofactors and collaborative transcription factors (TFs). Further elucidating the nexus between the AR and collaborative TFs may reveal new strategies targeting the AR directly or indirectly, such as targeting BET proteins or OCT1. However, appropriate preclinical models will be required to test the efficacy of these approaches. Fortunately, an increasing variety of patient-derived models, such as xenografts and organoids, are being developed for discovery-based research and preclinical drug screening. Here we review the mechanisms of drug resistance in the AR signaling pathway, the intersection with collaborative TFs, and the use of patient-derived models for novel drug discovery.

A Retrospective Observational Analysis of Overall Survival with Sipuleucel-T in Medicare Beneficiaries Treated for Advanced Prostate Cancer.

IntroductionSince sipuleucel-T approval in 2010, the treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) now includes the androgen-receptor signaling pathway inhibitors (ASPIs) abiraterone acetate or enzalutamide. In 2013 and 2014, these oral agents were approved for use in men with metastatic prostate cancer who had minimal to no symptoms. We compared overall survival (OS) in men who received their first mCRPC treatment using the Medicare Fee-for-Service 100% administrative claims research dataset with patient-level linkage to the National Death Index.MethodsThis retrospective cohort analysis (January 2013 to December 2017) included men who were chemo-naïve at treatment start in 2014 and who had continuous Medicare Parts A, B, and D eligibility during the 3-year observation period. We compared: first-line sipuleucel-T vs. first-line ASPIs and any-line sipuleucel-T vs. any-line ASPIs (without sipuleucel-T). We used a multivariable regression model to help control for potentially confounding factors while assessing survival outcomes.ResultsThe model included 6044 eligible men (average age 75–78 years) with similar disease severity; > 80% were white. Median OS, presented as sipuleucel-T vs. ASPI, was 35.2 vs. 20.7 months (n, 906 vs. 5092; any-line cohort) and 34.9 vs. 21.0 months (n, 647 vs. 4810; first-line cohort). Model outcomes indicated sipuleucel-T was associated with significantly prolonged OS compared with ASPIs: adjusted hazard ratio, 0.59 (95% CI 0.527–0.651) and 0.56 (0.494–0.627) for the any-line and first-line cohorts, respectively.ConclusionThis analysis suggests use of sipuleucel-T at any time was associated with improved OS compared with ASPI use alone. Of note, these analyses are intended as descriptive rather than definitive as this dataset contains limited data on key clinical factors. While selection bias is a risk in secondary claims data, this research provides important insight into real-world treatment outcomes.Electronic Supplementary MaterialThe online version of this article (10.1007/s12325-020-01509-5) contains supplementary material, which is available to authorized users.

295 Poster - Prognostic utility of androgen receptor signaling pathway in invasive breast cancer

Background: Androgen receptor (AR) and AR signaling pathway are thought to play a role in tumour progression and be potentially related to treatment responses and outcomes in invasive breast cancer. In present study, we investigated the clinicopathological significance of AR associated signaling pathway using the large transcriptomic database of early-stage invasive breast cancer.

Virtual Screening and Bioactivity Evaluation of Novel Androgen Receptor Antagonists From Anti-PCa Traditional Chinese Medicine Prescriptions.

Prostate cancer (PCa), a type of malignancy that arises in the prostate gland, is the most commonly diagnosed neoplasm and the second leading cause of cancer-related deaths in men. Acquisition of resistance to conventional therapy is a major problem for PCa patient treatment. Androgen receptor (AR) signaling pathway is necessary in the pathogenesis of prostate cancer, and there is a heightened interest in finding novel AR antagonists that target AR and its regulatory pathways. In our search for novel androgen receptor antagonists, we focus on the Traditional Chinese Medicine (TCM), which has been used for thousands of years to prove effective in the treatment of cancer. In this study, we collected 653 traditional Chinese medicine prescriptions that have certain therapeutic effect to prostate cancer, including the prescriptions and even the folk prescriptions. After summarizing the frequency of herbs and gathering the natural products contained in these prescriptions, we built a natural products database to do computer-aided virtual screening and drug-like evaluation to find potential AR antagonists. Totally 25 compounds were submitted to experimental biological activity tests. Through the MTT cell proliferation experiment, 5 chemicals were found to inhibit the proliferation of LNCaP cells in a concentration-dependent manner. Especially, MoL_11 was found to have good antagonistic activity and significantly inhibit fluorescence enzyme activity by the AR reporter gene experiment. Finally, the molecular dynamics simulation method was used to study the interaction between the most active compound MoL_11 and the wild-type and F876L mutant androgen receptor (WT/F876L AR), and it was found that F876L AR could not cause resistance to MoL_11.

Crosstalk Between AR and Wnt Signaling Promotes Castration-Resistant Prostate Cancer Growth.

IntroductionProstate cancer (PCa) is the most commonly diagnosed cancer and the third leading cause of cancer-related death in males in the United States. Despite the initial efficacy of androgen deprivation therapy in prostate cancer (PCa) patients, most patients progress to castration-resistant prostate cancer. However, the mechanisms underlying the androgen-independent progression of PCa remain largely unknown.MethodsIn this study, we established a PCa cell line (LNCaP-AI) by maintaining LNCaP cells under androgen-depleted conditions. To explore the cellular and molecular mechanisms of androgen-independent growth of PCa, we analyzed the gene expression patterns in androgen-independent prostate cancer (AIPC) compared with that in androgen-dependent prostate cancer (ADPC). KEGG pathway analysis revealed that Wnt signaling pathways were activated after androgen deprivation therapy (ADT). In vitro experiments showed that the inhibition of Wnt pathway reduced AIPC cell growth by inhibiting cell cycle progression and promoting apoptosis. Furthermore, WNT5A, LEF1 were identified as direct targets of AR by chromatin immunoprecipitation (ChIP) assay and public ChIP-seq datasets analysis.ResultsIn the present study, we found a regulatory mechanism through which crosstalk between androgen receptor (AR) and Wnt signals promoted androgen-independent conversion of PCa. The Wnt pathway was inhibited by androgen in androgen-dependent prostate cancer cells, but this blocking effect was not elicited in androgen-independent prostate cancer (AIPC) cells. Moreover, Wnt pathway genes WNT5A and LEF1 were directly downregulated by AR. In vitro experiments showed that inhibition of the Wnt pathways repressed AIPC cell growth by inhibiting cell cycle progression and promoting apoptosis. We found that WNT5A and LEF1 were downregulated in low-grade PCa but upregulated in metastatic PCa.ConclusionIn summary, we revealed that crosstalk between AR and Wnt signaling pathways promotes androgen-independent growth of PCa, which may provide novel therapeutic opportunities for castration-resistant prostate cancer.

Splicing factor PRPF6 upregulates oncogenic androgen receptor signaling pathway in hepatocellular carcinoma.

Androgen receptor (AR) signaling is considered to be crucial for the pathogenesis of hepatocellular carcinoma (HCC) with obvious sexual dimorphism. Pre‐mRNA processing factor 6 (PRPF6) was identified as a coactivator of AR. However, the molecular mechanism underlying the modulation function of PRPF6 on AR‐mediated transcriptional activity in HCC needs to be further clarified. In this study, we analyzed data from The Cancer Genome Atlas to show that PRPF6 is highly expressed in HCC. . Our data indicated that PRPF6 interacts with AR/AR splice variants (AR‐Vs) and upregulates AR/AR splice variant 7‐mediated transcriptional activity even without dihydrotestosterone treatment. We observed that AR is obviously induced by androgen treatment and is mainly expressed in the nucleus in HCC‐derived cell lines. Moreover, overexpression of PRPF6 enhances AR expression accompanied with the increase of AR‐Vs expression. We provided evidence that PRPF6 participates in upregulating AR self‐transcription. PRPF6 facilitates the recruitment of AR to the androgen responsive element region of the AR gene. Finally, PRPF6 depletion inhibits cell proliferation in HCC cells and mouse xenografts. Taken together, our results suggest that PRPF6 as a splicing factor enhances AR self‐transcription, thereby coactivating oncogenic AR/AR‐Vs actions in HCC.

Abstract 274: Multifaceted function of microRNA-299-3p fosters an antitumor environment through modulation of androgen receptor and VEGFA signaling pathways in prostate cancer cells

Abstract MicroRNAs (miRNAs) play crucial roles in the regulation of prostate cancer (PCa) through modulation of signaling pathways. Androgen receptor (AR) signaling is central to PCa and PCa therapy. The therapeutic suitability of miRNAs that target AR has not been investigated thoroughly. Here, we illustrate the clinical relevance, functional significance and therapeutic benefit of miR-299-3p, an AR targeting microRNA, in PCa progression. We noted a loss of expression of miR-299-3p in prostate tumors compared to noncancerous prostate tissue in clinical specimens. Studies on the impact of miR-299-3p restoration on AR function, phenotypic changes associated with cancer progression and involvement of the downstream components of the AR signaling pathway were conducted using in vitro and in vivo model systems. Replenishment of miR-299-3p in C4-2B, 22Rv-1, and PC-3 cells contributed to cell cycle arrest, reduced cell proliferation, migration and increased expression of apoptotic markers. Additionally, expression of miR-299-3p reduced AR, PSA and VEGFA expression. AGO-RNA pulldown experiment showed enrichment of AR, VEGFA and miR-299-3p in the RISC in the extracts of C4-2B cells overexpressing miR-299-3p. Overexpression of miR-299-3p inhibited epithelial-mesenchymal transition signaling, through inhibition of expression of Slug, TGF-Β3, phospho-AKT, and phospho-PRAS40 and up-regulation of E-cadherin. Replenishment of miR-299-3p showed reduced tumor growth in xenograft mice models. Furthermore, we also tested the benefit of miR-299-3p restoration in combination treatment with enzalutamide and docetaxel which showed a synergistic effect on drug sensitivity. In conclusion, this study has identified novel mechanisms of antitumor and antimigration functions of miR-299-3p through modulation of AR and VEGFA signaling pathways which leads to improved drug sensitivity of PCa. Citation Format: Kavya Ganapathy, Stephen Staklinski, Md Faqrul Hasan, Richard Ottman, Thomas Andl, Anders Berglund, Jong Park, Ratna Chakrabarti. Multifaceted function of microRNA-299-3p fosters an antitumor environment through modulation of androgen receptor and VEGFA signaling pathways in prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 274.

Abstract 4850: Targeting prostate cancer with the CDK4 and CDK6 inhibitor abemaciclib

Abstract Background: Prostate cancer (PCa) is a leading cause of cancer death in men and represents a substantial public health burden [1]. Most PCa are primarily dependent on androgen receptor (AR) activity and castration is an effective approach to treat PCa patients. Despite the recent significant treatment advances, PCa inevitably becomes androgen-independent and progresses to the castration-resistant disease state (CRPC), the deadliest form of the disease [2]. Progression of the disease to castration-resistance is often mediated by a reactivation of AR signaling pathway [3]. Upon androgen stimulation, expression of D-type cyclin is up-regulated which results in an increased cyclin-dependent kinase 4 and 6 (CDK4/6) activity and stimulation of the cell cycle. [4]; Thus, inhibition of CDK4/6 may represent an effective strategy to delay or overcome primary androgen resistance. Abemacicilb is a CDK4 and CDK6 inhibitor with a clinical safety profile allowing continuous dosing to achieve sustained target inhibition [5]. Abemaciclib is FDA-approved for the treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer [6,7]. Methods: The anti-proliferative activity of the abemaciclib was evaluated using iodide staining in a panel of 15 PCa cell lines. In order to get new insights on abemaciclib effects, deeper in vitro analysis was carried out in LNCaP, PC-3 and 22RV1, as ADT responding and resistant PCa cell models, respectively. Cell cycle analysis was done by FACS and High Content Imaging; cellular signaling was assessed by Western blotting. Apoptosis was measured by detection of caspase 3 and Tunnel assay. 22RV1 xenograft mouse model was used to evaluate abemaciclib efficacy in vivo. Results: Anti-proliferative activity of abemaciclib was observed across a panel of PCa cell lines, mainly in hormone receptor positive (AR+) cell lines. Overall, abemaciclib efficiently inhibited CDK4 and CDK6 which prevented the phosphorylation of Rb with the consequent effect in cell cycle and induced a G1 cell cycle arrest. Prolonged treatment promoted a marked senescence phenotype indicated by an increased b-galactosidase staining and morphological changes to result ultimately in apoptosis. In 22RV1 xenograft models, abemaciclib significantly reduced tumor growth. Taken together these data provide insights on sensitivity of PCa models to abemaciclib and its mode of action, demonstrating the potential of this drug for the treatment of prostate cancer patients. Conclusions: Abemaciclib inhibits proliferation of AR positive prostate cancer cell lines by inducing cell cycle arrest mediated by inhibition of Rb phosphorylation. Abemaciclib is a CDK4/6 inhibitor with potential to treat prostate cancer by blocking cell proliferation leading to induction of senescence and apoptosis. Citation Format: Raquel Torres-Guzmán, Carmen Baquero, Maria Patricia Ganado, Carlos Marugán, Huimin Bian, Yi Zeng, Ramón Rama, Jian Du, Maria José Lallena. Targeting prostate cancer with the CDK4 and CDK6 inhibitor abemaciclib [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4850.

Systematic analysis of miRNAs in patients with postmenopausal osteoporosis

MicroRNAs (miRNAs) represent RNA species found in serum. Many miRNAs were observed that were related to osteoporosis and osteopenia. However, expression and function analysis of miRNAs in postmenopausal osteoporosis (PMOP) remain unaddressed. We first compared the miRNA expression of blood samples in postmenopausal women with osteopenia or with osteoporosis via analysis of GSE64433. Bioinformatics analyses were conducted to get the key miRNAs and their functions and pathways. 331 miRNAs were being identified as differentially expressed miRNAs. Among these, 122 miRNA (36.86%) were up-regulated, and the remaining 209 miRNAs (63.14%) were down-regulated. 105 genes were predicted as the targets of these miRNAs. GO enrichment analysis results showed that the miRNAs mainly enriched in DNA binding, ATP binding, gene expression, regulation of the apoptotic process, chromatin binding, and protein kinase binding. KEGG enrichment analysis results demonstrated that the miRNAs mainly enriched in the TGF beta signaling pathway, wnt signaling pathway, JAK-STAT signaling pathway, and androgen receptor signaling pathway. This study identified the abundant differentially expressed miRNAs in the blood samples of postmenopausal women with osteopenia or with osteoporosis. This study may contribute to getting new diagnostic and therapeutic strategies for PMOP.

Rapamycin inhibits AR signaling pathway in prostate cancer by interacting with the FK1 domain of FKBP51

Reactivation of the androgen receptor signaling pathway in the emasculated environment is the main reason for the occurrence of castration-resistant prostate cancer (CRPC). The immunophilin FKBP51, as a co-chaperone protein, together with Hsp90 help the correct folding of AR. Rapamycin is a known small-molecule inhibitor of FKBP51, but its effect on the FKBP51/AR signaling pathway is not clear. In this study, the interaction mechanism between FKBP51 and rapamycin was investigated using steady-state fluorescence quenching, X-ray crystallization, MTT assay, and qRT-PCR. Steady-state fluorescence quenching assay showed that rapamycin could interact with FKBP51. The crystal of the rapamycin-FKBP51 complex indicated that rapamycin occupies the hydrophobic binding pocket of FK1 domain which is vital for AR activity. The residues involving rapamycin binding are mainly hydrophobic and may overlap with the AR interaction site. Further assays showed that rapamycin could inhibit the androgen-dependent growth of human prostate cancer cells by down-regulating the expression levels of AR activated downstream genes. Taken together, our study demonstrates that rapamycin suppresses AR signaling pathway by interfering with the interaction between AR and FKBP51. The results of this study not only can provide useful information about the interaction mechanism between rapamycin and FKBP51, but also can provide new clues for the treatment of prostate cancer and castration-resistant prostate cancer.

Hormonal regulation in male androgenetic alopecia-Sex hormones and beyond: Evidence from recent genetic studies.

Male-pattern hair loss, also termed androgenetic alopecia (AGA), is a highly prevalent age-related condition that is characterized by a distinct pattern of hair loss from the frontotemporal and vertex regions of the scalp. The phenotype is highly heritable and hormone dependent, with androgens being the recognized critical hormonal factor. Numerous molecular genetic studies have focused on genetic variation in and around the gene that encodes the androgen receptor. More recently, however, the availability of high-throughput molecular genetic methods, novel methods of data analysis and sufficiently large sample sizes have rendered possible the systematic investigation of the contribution of other components of the androgen receptor pathway or hormonal pathways beyond the androgen receptor signalling pathways. Over the past decade, genome-wide association studies of increasingly large cohorts have enabled the genome-wide identification of genetic risk factors for AGA, and yielded unprecedented insights into the underlying pathobiology. The present review discusses some of the most intriguing genetic findings on the relevance of (sex)hormonal signalling in AGA.

A Novel Micropeptide Encoded by Y-Linked LINC00278 Links Cigarette Smoking and AR Signaling in Male Esophageal Squamous Cell Carcinoma.

Long noncoding RNAs (lncRNA) have been shown to play critical roles in many diseases, including esophageal squamous cell carcinoma (ESCC). Recent studies have reported that some lncRNA encode functional micropeptides. However, the association between ESCC and micropeptides encoded by lncRNA remains largely unknown. In this study, we characterized a Y-linked lncRNA, LINC00278, which was downregulated in male ESCC. LINC00278 encoded a Yin Yang 1 (YY1)-binding micropeptide, designated YY1BM. YY1BM was involved in the ESCC progression and inhibited the interaction between YY1 and androgen receptor (AR), which in turn decreased expression of eEF2K through the AR signaling pathway. Downregulation of YY1BM significantly upregulated eEF2K expression and inhibited apoptosis, thus conferring ESCC cells more adaptive to nutrient deprivation. Cigarette smoking decreased m6A modification of LINC00278 and YY1BM translation. In conclusion, these results provide a novel mechanistic link between cigarette smoking and AR signaling in male ESCC progression. SIGNIFICANCE: Posttranscriptional modification of a micropeptide-encoding lncRNA is negatively impacted by cigarette smoking, disrupting negative regulation of the AR signaling pathway in male ESCC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2790/F1.large.jpg.See related commentary by Banday et al., p. 2718.

CUDC-907, a novel dual PI3K and HDAC inhibitor, in prostate cancer: Antitumour activity and molecular mechanism of action.

Targeting the androgen receptor (AR) signalling pathway remains the main therapeutic option for advanced prostate cancer. However, resistance to AR‐targeting inhibitors represents a great challenge, highlighting the need for new therapies. Activation of the PI3K/AKT pathway and increased expression of histone deacetylases (HDACs) are common aberrations in prostate cancer, suggesting that inhibition of such targets may be a viable therapeutic strategy for this patient population. Previous reports demonstrated that combination of PI3K inhibitors (PI3KIs) with histone deacetylase inhibitors (HDACIs) resulted in synergistic antitumour activities against preclinical models of prostate cancer. In this study, we demonstrate that the novel dual PI3K and HDAC inhibitor CUDC‐907 has promising antitumour activity against prostate cancer cell lines in vitro and castration‐resistant LuCaP 35CR patient‐derived xenograft (PDX) mouse model in vivo. CUDC‐907‐induced apoptosis was partially dependent on Mcl‐1, Bcl‐xL, Bim and c‐Myc. Further, down‐regulation of Wee1, CHK1, RRM1 and RRM2 contributed to CUDC‐907‐induced DNA damage and apoptosis. In the LuCaP 35CR PDX model, treatment with CUDC‐907 resulted in significant inhibition of tumour growth. These findings support the clinical development of CUDC‐907 for the treatment of prostate cancer.

Exploring the Role of Asp1116 in Selective Drug Targeting of CREBcAMP- Responsive Element-binding Protein Implicated in Prostate Cancer.

The selective targeting of CREB-cAMP-responsive element-binding protein (CBP) has recently evolved as a vital therapeutic approach for curtailing its aberrant upregulation associated with the development of prostate cancer. Inhibition of CBP has been discovered to be an important therapeutic option in androgen receptor signalling pathway mediated prostate cancer. Y08197, a novel selective inhibitor of CBP, has shown promising therapeutic outcome in prostate carcinogenesis over non-selective analogues such as CPI-637. Herein, we used molecular dynamics simulation to gain insights into the mechanistic and selective targeting of Y08197 at the bromodomain active site. Molecular Mechanics/ Poisson-Boltzmann Surface Area (MM/PBSA) analysis revealed a similar inhibitory effect between Y08197 and CPI-637. Furthermore, in exploring the selective affinity of Y08197 towards CBP in combination with Bromodomain and PHD finger-containing protein 1(BRPF1), our findings highlighted Asp1116 as the 'culprit' residue responsible for this selective targeting. Upon binding, Asp1116 assumed a conformation that altered the architecture of the bromodomain active site, thereby orienting the helices around the active site in a more compacted position. In addition to some specific structural perturbations mediated by Asp1116 on the dynamics of CBP, our study revealed that the strong hydrogen bond interaction (N-H...O) elicited in CBP-Y08197 sequestered Y08197 tightly into the CBP bromodomain active site. Conclusively, the inhibition and selective pattern of Y08197 can be replicated in future structure-based CBP inhibitors and other bromodomain implicated in carcinogenesis.

Berberine Ameliorates Prenatal Dihydrotestosterone Exposure-Induced Autism-Like Behavior by Suppression of Androgen Receptor.

Many epidemiology studies have shown that maternal polycystic ovary syndrome (PCOS) results in a greater risk of autism spectrum disorders (ASD) development, although the detailed mechanism remains unclear. In this study, we aimed to investigate the potential mechanism and provide a possible treatment for PCOS-mediated ASD through three experiments: Experiment 1: real-time PCR and western blots were employed to measure gene expression in human neurons, and the luciferase reporter assay and chromatin immunoprecipitation (ChIP) was used to map the responsive elements on related gene promoters. Experiment 2: pregnant dams were prenatally exposed to dihydrotestosterone (DHT), androgen receptor (AR) knockdown (shAR) in the amygdala, or berberine (BBR), and the subsequent male offspring were used for autism-like behavior (ALB) assay followed by biomedical analysis, including gene expression, oxidative stress, and mitochondrial function. Experiment 3: the male offspring from prenatal DHT exposed dams were postnatally treated by either shAR or BBR, and the offspring were used for ALB assay followed by biomedical analysis. Our findings showed that DHT treatment suppresses the expression of estrogen receptor β (ERβ) and superoxide dismutase 2 (SOD2) through AR-mediated hypermethylation on the ERβ promoter, and BBR treatment suppresses AR expression through hypermethylation on the AR promoter. Prenatal DHT treatment induces ERβ suppression, oxidative stress and mitochondria dysfunction in the amygdala with subsequent ALB behavior in male offspring, and AR knockdown partly diminishes this effect. Furthermore, both prenatal and postnatal treatment of BBR partly restores prenatal DHT exposure-mediated ALB. In conclusion, DHT suppresses ERβ expression through the AR signaling pathway by hypermethylation on the ERβ promoter, and BBR restores this effect through AR suppression. Prenatal DHT exposure induces ALB in offspring through AR-mediated ERβ suppression, and both prenatal and postnatal treatment of BBR ameliorates this effect. We conclude that BBR ameliorates prenatal DHT exposure-induced ALB through AR suppression, this study may help elucidate the potential mechanism and identify a potential treatment through using BBR for PCOS-mediated ASD.

Effect of Bicalutamide on the proliferation and invasion of human triple negative breast cancer MDA-MB-231 cells.

Previous studies have shown androgen receptor (AR) is associated with the occurrence, development, recurrence, metastasis, and prognosis of triple negative breast cancer (TNBC). More and more experts have noticed that AR signaling pathway plays an important role in the occurrence and development of TNBC. The purpose of this study is to detect the inhibitory efficacy and mechanism of Bicalutamide on the proliferation and invasion of TNBC cells.MDA-MB-231 cells of human breast cancer cells were treated with 0, 25, 100 μmol/L of Bicalutamide, cell proliferation assay was performed to assess cell proliferation viability by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide assay and cell invasion was evaluated by Transwell assay. Meanwhile, flow cytometric analysis and western blotting were performed to investigate the mechanism of Bicalutamide on the proliferation and invasion of MDA-MB-231 cells.Bicalutamide could efficiently inhibit the proliferation and invasion of MDA-MB-231 cells in a dose-dependent manner. In addition, Bicalutamide could significantly induce the cell cycle arrest at G0/G1 phase and decrease the protein expression of AR, cyclin D1, matrix metalloprotease-2 (MMP-2), and matrix metalloprotease-9 (MMP-9).The present study indicated the Bicalutamide inhibited the proliferation and invasion process of triple negative breast cancer cells by targeting AR signaling pathway and down-regulating MMP-2/-9 protein expression levels.