RNA-seq control (sgNT) and TLE3KO (sgTLE3) cells treated with 10 uM enzalutamide or vehicle
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE130246 | GEO | 2020/01/27
REPOSITORIES: GEO
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Project description:RNA-seq control (sgNT) and TLE3KO (sgTLE3) cells treated with 10 uM enzalutamide or vehicle
| PRJNA534447 | ENA
Project description:Enzalutamide (formerly MDV3100 and available commercially as Xtandi), a novel androgen receptor (AR) signaling inhibitor, blocks the growth of castration-resistant prostate cancer (CRPC) in cellular model systems and was shown in a clinical study to increase survival in patients with metastatic CRPC. Enzalutamide inhibits multiple steps of AR signaling: (1) binding of androgens to AR, (2) AR nuclear translocation, and (3) association of AR with DNA. Here we used Affymetrix human genome microarray technology to investigate the global programme of gene expression of LNCaP cells in response to enzalutamide alone and in the context of DHT-stimulated androgen receptor gene expression. LNCaP cells were grown in RPMI 1640 supplemented with 5% hormone depleted FBS and treated with vehicle (control sample) , DHT (100 nM), enzalutamide (1 or 10 M-BM-5M) or DHT (100 nM) plus enzalutamide (1 or 10 M-BM-5M)for 16 hours for RNA extraction and hybridization. Each condition was done in triplicate.
2013-04-01 | E-GEOD-44905 | biostudies-arrayexpress
Project description:In order to identify AR-repressed genes that are activated by enzalutamide in t-NEPC cell lines, we cultured enza-resistant MR42D cells in the absence of enzalutamide for 72 hours, then added back either enzalutamide or vehicle and cultured for an additional 24 hours. Then we performed chromatin immunoprecipitation sequencing (ChIP-seq) pulling down AR, BRD4, and H3K27Ac. To identify potential NEPC genes suppressed by the AR, we compared AR DNA occupancy from the vehicle and enzalutamide treatments to identify regions where AR was evicted in response to enzalutamide. Similarly to determine the role of histone acetylation on NEPC gene activation in t-NEPC lines, we examined differential DNA-binding of the BRD4 acetylated lysine reader, and differential acetylation of the active enhancer mark H3K27Ac in response to enzalutamide treatment.
2021-06-22 | GSE147875 | GEO
Project description:We established an enzalutamide-resistant C4-2b prostate cell line that has an active androgen receptor by maintaining the C4-2b cell line in serially increasing concentrations of enzalutamide. Among the CRPC cell lines, we selected the C4-2b cell line because it is known to have AR variants, and we desired to identify enzymes with the ability to regulate the activity of AR variants as well as the wild type AR. After 2 months, we acquired resistant cells in even 10 uM enzalutamide. After validation of enzalutamide-resistant character, we analyzed global changes in mRNA expression by using quantitative mRNA-sequencing analysis.
2020-02-01 | GSE110802 | GEO
Project description:Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) â?? the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. RNA-seq profiles of prostate cancer cell lines to understand gene expression associated with enzalutamide treatment
2016-06-10 | E-GEOD-69896 | biostudies-arrayexpress
Project description:To identify mechanisms that contribute to lineage plasticity and t-NEPC, we focused on enza-resistant cell lines with persistent AR expression that have features of lineage plasticity, including high expression of NEPC markers: the MR42D and MR42F cell lines. We cultured these enzalutamide resistant lines, which are usually maintained in medium with enzalutamide, without enzalutamide for 72 hors to "washout" the effects of enzalutamide, and then either enzalutamide or vehicle was added back to the growing media for 24 hours. Enzalutamide sensitive lines LNCaP and V16D were treated with either enzalutamide or vehicle for 24 hours. Enzalutamide reversibly increased expression neuronal markers in MR42D and MR42F cells, but not enza-sentitive LNCaP and V16D cells, suggesting that the AR may negatively regulate neuronal gene expression in these t-NEPC cells. Moreover, bromodomain inhibitors (BETi) ARV-771 and JQ1 reduced expression of NEPC target genes in MR42D cells.
2021-06-22 | GSE147876 | GEO
Project description:Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand binding domain (LBD)-binding antagonists, are inactivated by common resistance -mechanisms. It is important to develop next-generation mechanistically-distinct drugs to treat castration- and drug- resistant prostate cancers. Here, we describe a second-generation AR pan-antagonist (UT-34) that degrades the AR and AR splice variants. UT-34 inhibits the wild-type and LBD mutant ARs comparably and inhibits the in vitro proliferation and in vivo growth of enzalutamide-sensitive and resistant prostate cancer xenografts. In preclinical models, UT-34 induced the regression of enzalutamide-resistant tumors at doses when the AR is degraded; but, at lower doses when the AR is just antagonized, it inhibits, without shrinking, the tumors. This indicates that degradation might be a prerequisite for tumor regression. Mechanistically, UT-34 promotes a conformation that is distinct from the LBD-binding competitive antagonist, enzalutamide, and degrades the AR through the ubiquitin proteasome mechanism. UT-34 has a broad safety margin and exhibits no cross-reactivity with G-Protein Coupled Receptor, kinase, and nuclear receptor family members. Collectively, UT-34 exhibits the properties necessary for a next-generation prostate cancer drug. MR49F cells (n=3-4/group) were maintained in charcoal-stripped serum containing medium for 48 hours and treated with vehicle, 0.1 nM R1881, or 10 uM of UT-34 in combination with 0.1 nM R1881. Twenty four hours after treatment, the cells were harvested, RNA was isolated and expression of genes was measured using microarray (Affymetrix Clarion S) UT-34 is a selective androgen receptor degrader that degrades and antagonizes the AR. UT-34 binds to the AF-1 domain of the AR and degrades the AR through ubiquitin proteasome pathways. The transcriptome study was performed to evaluate the ability of UT-34 to antagonize the enzalutamide-resistant AR function.
2019-12-31 | GSE133119 | GEO
Project description:In this study, we found the efficacy of AR-targeting drugs largely depended on the context of AR (Androgen Receptor) and ERα (Estrogen Receptor) status. Enzalutamide, an AR blocker, had a better inhibition effect on ER+ cells with lower AR expressed compared to cells expressed higher AR. To explore the mechanism of action of Enzalutamide, we performed ChIP-seq to illustrate the AR and ER genomic bindings after Enzalutamide treatment in both MCF7 and MCF7 with AR over expression (AROE) cells. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for androgen receptor (AR) and Estrogen receptor (ER) after Enzalutamide treatment in MCF7 and MCF7 AROE cells
2022-11-28 | GSE200300 | GEO
Project description:RNA-Seq analysis of prostate cancer cell line LNCaP treated with vehicle (C), androgen (R), androgen and IMTPPE (R + IMTPPE), androgen and JJ-(+)-450 (androgen + (-)450), androgen and JJ-(-)450 (androgen + (-)450), androgen and enzalutamide (androgen +Enz). To evaluate if our compounds can inhibit AR function specifically and completely, LNCaP mRNA profiles of cells treated with IMTPPE, (+)-JJ-450 and (-)-JJ-450, comparing to enzalutamide. RNA isolation was performed using RNeasy Mini kit (Qiagen), RNA Sequencing was carried out by Genomics Research Core of University of Pittsburgh using Illumina NextSeq 500 system. The sequence reads that passed FASTQC were analyzed at the transcript level. Each sample was mapped to the Human Ensembl reference genome GRCh38. We definied different expression genes with a fold change ≥2.0 and FDR <0.05. Both (-)-JJ-450 and enzalutamide are very specific to AR, with 56 and 186 DE genes comparing to control samples respectively. IMTPPE and (+)-JJ-450 can inhibit most of the androgen responsive genes, but also some other genes were affected. (-)-JJ-450 is a novel compound inhibts AR function specifically and completely, and it is a potential lead compound for the treatment of CRPC, including those resistant to enzalutamide.
2019-06-06 | GSE115395 | GEO
Project description:Enzalutamide, a second-generation androgen receptor (AR) antagonist, has demonstrated clinical benefit in men with prostate cancer. However, it only provides a temporary response and modest increase in survival, indicating a rapid evolution of resistance. Previous studies suggest that enzalutamide may function as a partial transcriptional agonist, but the underlying mechanisms for enzalutamide-induced transcription remain poorly understood. Here, we show that enzalutamide stimulates expression of a novel subset of genes distinct from androgen-responsive genes. Treatment of prostate cancer cells with enzalutamide enhances recruitment of pioneer factor GATA2, AR, Mediator subunits MED1 and MED14, and RNA Pol II to regulatory elements of enzalutamide-responsive genes. Mechanistically, GATA2 functions in directing AR, Mediator and Pol II loading to enzalutamide-responsive gene loci. Importantly, the GATA2 inhibitor K7174 inhibits enzalutamide-induced transcription by decreasing binding of the GATA2/AR/Mediator/Pol II transcriptional complex, contributing to sensitization of prostate cancer cells to enzalutamide treatment. Our findings provide mechanistic insight into the future combination of GATA2 inhibitors and enzalutamide for improved AR-targeted therapy.
2019-09-03 | GSE125014 | GEO