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Differential redulation of gene expression by an RTI SARM and canonical agonist of androgen receptor

ABSTRACT: We have previously identified a family of novel androgen receptor (AR) ligands that, upon binding, enable AR to adopt structures distinct from that observed in the presence of canonical agonists. In this report, we describe the use of these compounds to establish a relationship between AR structure and biological activity with a view to defining a rational approach with which to identify useful Selective Androgen Receptor Modulators (SARMs). As one of the approaches, we used a DNA microarray analysis to demonstrate that differently conformed receptors facilitate distinct patterns of gene expression in LNCaP cells. Interestingly, we observed a complete overlap in the identity of genes expressed following treatment with mechanistically distinct AR ligands. However, it was differences in the kinetics of gene regulation that distinguished these compounds. Follow-up studies, in cell-based assays of AR action, confirmed the importance of these alterations in gene expression. Together these studies demonstrate an important link between AR structure, gene expression and biological outcome. Keywords: Comparative gene expression analysis, cell culture, prostate carcinoma, androgen receptor, selective modulators of androgen receptor, SARM

ORGANISM(S): Homo sapiens

PROVIDER: GSE4636 | GEO | 2006/04/11

SECONDARY ACCESSION(S): PRJNA95313

REPOSITORIES: GEO

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Transcription profiling of human LNCaP cells treated with DHT, RTI-6413-018 or vehicle to identify useful Selective Androgen Receptor Modulators (SARMs)

Project description:We have previously identified a family of novel androgen receptor (AR) ligands that, upon binding, enable AR to adopt structures distinct from that observed in the presence of canonical agonists. In this report, we describe the use of these compounds to establish a relationship between AR structure and biological activity with a view to defining a rational approach with which to identify useful Selective Androgen Receptor Modulators (SARMs). As one of the approaches, we used a DNA microarray analysis to demonstrate that differently conformed receptors facilitate distinct patterns of gene expression in LNCaP cells. Interestingly, we observed a complete overlap in the identity of genes expressed following treatment with mechanistically distinct AR ligands. However, it was differences in the kinetics of gene regulation that distinguished these compounds. Follow-up studies, in cell-based assays of AR action, confirmed the importance of these alterations in gene expression. Together these studies demonstrate an important link between AR structure, gene expression and biological outcome. In this experiment LNCaP cells (400,000 per 75 cm2 flask) were first incubated in DMEM/8% charcoal-stripped serum to reduce the background hormone exposure, and then were treated with Vehicle (ethanol), DHT (10 nM) or RTI-6413-018 (100 nM). Treatment was done for 6 and 24 hrs. At the end of treatment, cells were collected by trypsization and immediately frozen in liquid nitrogen. Isolation of mRNA was performed using Qiagen Oligotex midi kit. cRNA synthesis, labeling and hybridization were performed by Expression Analysis Institute, Durham, NC. Samples were hybridized to Affymetrix HG.U133 A and B chips. Experiment was repeated three times.

2007-12-19 | E-GEOD-4636 | biostudies-arrayexpress

Androgen receptor is a back-door inhibitor of Androgen Receptor is a Backdoor Inhibitor of Wildtype and Mutant Estrogen Receptors in Refractory Hormone Receptor-Positive Breast Cancers

Project description:HCI-13 patient-derived xenograft was treated with vehicle or a tissue-selective androgen receptor modulator (SARM), enobosarm. RNA was extracted from the tumors and microarray was performed. Objective: The objective of the study is to determine the effect of an androgen receptor (AR) agonist or a selective AR modulator (SARM) on hormone receptor-positive breast cancer growth in preclinical models and to determine the underlying mechanism of action.

2019-07-31 | GSE126318 | GEO

Overcoming Resistance to Anabolic SARM therapy in Experimental Cancer Cachexia with an HDAC Inhibitor

Project description:No approved therapy exists for cancer-associated cachexia. The colon-26 mouse model of cancer cachexia mimics recent late stage clinical failures of anabolic anti-cachexia therapy, and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx-024. The histone deacetylase inhibitor (HDACi) AR-42 exhibited anti-cachectic activity in this model. We explored combined SARM/AR-42 therapy as an improved anti-cachectic treatment paradigm. A reduced dose of AR-42 provided limited anti-cachectic benefits, but, in combination with GTx-024, significantly improved body weight, hind limb muscle mass, and grip strength versus controls. AR-42 suppressed the IL-6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx-024-mediated β-catenin target gene regulation was apparent in cachectic mice only when combined with AR-42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.

2019-11-20 | GSE138464 | GEO

Global modulation of signaling pathways by SARM RAD140 in AR/ER+ breast cancer xenografts

Project description:These data demonstrates the regulation of AR and ER pathways by the SARM RAD140 and suggested a unique mechanism of action of RAD140 via the AR-mediated transcription repression.

2017-09-26 | GSE104177 | GEO

Expression data of treated LNCaP-abl cells

Project description:We introduce a family of multivalent peptidomimetic conjugates that modulate the activity of the androgen receptor (AR). Bioactive ethisterone ligands were conjugated to a set of sequence-specific peptoid oligomers. Certain multivalent peptoid conjugates enhance AR-mediated transcriptional activation. We identify a linear and a cyclic conjugate that exhibit potent anti-proliferative activity in LNCaP-abl cells, a model of therapy-resistant prostate cancer. The linear conjugate blocks AR action by competing for ligand binding. In contrast, the cyclic conjugate is active despite its inability to compete against endogenous ligand for binding to AR in vitro, suggesting a non-competitive mode of action. These results establish a versatile platform to design competitive and non-competitive AR modulators with potential therapeutic significance. We use microarray analysis to further elucidate the mechanism of AR antagonism and show that the compounds (cyc and n=8) are distinct. We used microarray analysis to see genone-wide effects on LNCaP-abl cells with moduators of AR activity LNCaP-abl cells were treated with compound and RNA was extracted and hybridized on Affymetrix microarrays Treatments: Vehicle is just Ethanol treated LNCaP-abl cells that were used as a control. n=8 and cyc are peptoid conjugates that modulate AR activity. n=8 is linear and cyc is a cyclic compounds. We wanted to look at gene expression when LNCaP-abl cells were treated with these compounds to show that they are distinct. C3 is a small molecule that inhibits the interaction between AR and beta-catenin (co-regulator protein). Initial results with this compound show potent anti-proliferative activity in LNCaP-abl cells and we wanted to further investigate the mechanism of action of this compound.

2012-12-21 | E-GEOD-37796 | biostudies-arrayexpress

Expression data of treated LNCaP-abl cells

2012-12-21 | GSE37796 | GEO

Identification of a novel cofactor, SH3YL1, that functions through interaction with the androgen receptor N-terminal polyproline domain

Project description:Nuclear receptor (NR)-mediated transcription is a dynamic process that is regulated by the binding of distinct ligands that induce conformational changes in the NR. These molecular alterations lead to the recruitment of unique cofactors (coactivators or corepressors) that control the expression of NR-regulated genes. Here, we show that a stretch of proline residues located within the N-terminus of AR is necessary for maximal androgen-mediated prostate cancer cell growth and migration. Furthermore, this polyproline domain is necessary for the expression of a subset of AR-target genes, but is dispensable for classical AR-mediated gene transcription. Using T7 phage display, we subsequently identified a novel AR-interacting protein, SH3YL1, whose interaction with AR is dependent upon this polyproline domain. Like the AR polyproline domain, SH3YL1 was required for maximal androgen-mediated cell growth and migration. Microarray analysis revealed that SH3YL1 also regulated a subset of AR-modulated genes. Correspondingly, we identified ubinuclein1 (UBN1), a key member of a histone H3.3 chaperone complex, as a transcriptional target of AR/SH3YL1. Moreover, UBN1 was necessary for maximal androgen-mediated proliferation and migration. Collectively, our data link a specific surface located within AR’s N-terminus to the recruitment of a novel cofactor, SH3YL1, which is required for the androgen-mediated expression of UBN1. Importantly, this signaling network was important for both androgen-mediated prostate cancer cell growth and migration. This work is significant because it could aid in the development of selective androgen receptor modulators (SARMs) and have therapeutic implications for AR-driven diseases.

2015-08-20 | GSE64885 | GEO

Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer

Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.

2023-10-11 | MTBLS8034 | MetaboLights

Effects of anti-androgenic compounds on zebrafish insulin mutants

Project description:Aiming to identify insulin-independent modulators of glucose homeostasis, we performed a drug screen on zebrafish insulin (ins) mutants and identified androgen receptor (AR) antagonists. To investigate how AR antagonism mediates glucose level reduction in ins mutants, we evaluated the effects of antagonist treatment using transcriptomic studies. RNA-Seq analyses were performed on 120 hours post fertilization (hpf) ins mutants treated with Flutamide or Cyproterone starting at 84 hpf compared to vehicle (DMSO) treated mutants.

2018-12-21 | E-MTAB-7283 | biostudies-arrayexpress

Genome-wide analysis of SUMOylation effects on androgen receptor (AR) binding in HEK293 cells (ChIP-seq)

Project description:Androgen receptor (AR) plays an important regulatory role during prostate cancer development. ARM-bM-^@M-^Ys transcriptional activity is regulated by androgenic ligands, but also by post-translational modifications. To study the role of the AR SUMOylation in genuine chromatin environment, we compared androgen-regulated gene expression and AR chromatin occupancy in PC-3 prostate cancer and HEK293 cell lines stably expressing wild-type (wt) or SUMOylation site-mutated AR (AR-K386R,K520R). Our genome-wide gene expression analyses reveal that the SUMOylation modulates the AR function in a target gene and pathway selective manner. The transcripts that are differentially regulated by androgen and SUMOylation are linked to cellular movement, cell death, cellular proliferation, cellular development and cell cycle. In line with these data, SUMOylation mutant AR cells proliferate faster and are more sensitive to apoptosis. Moreover, ChIP-seq analyses show that the SUMOylation modulates the chromatin occupancy of AR on many loci in a fashion that parallels with their differential androgen-regulated expression. De novo motif analyses show that other transcription factor-binding motifs are differentially enriched at the wtAR- and the AR-K386R,K520R-preferred genomic binding positions. Taken together, our data indicate that SUMOylation does not simply repress the AR activity, but it regulates ARM-bM-^@M-^Ys interaction with the chromatin and the receptorM-bM-^@M-^Ys target gene selection. Androgen receptor (AR) genomic binding was studied in wild-type AR (wtAR) or SUMOylation-deficient AR (AR-K2R) stably expressing cells HEK293 cells, in biological dublicates. Cells were treated 40 min either with 10 nM R1881 or EtOH (vehicle) and input was used as control (FRT_input GSM1176703).

2014-07-03 | E-GEOD-54109 | biostudies-arrayexpress

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