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Chromatin Occupancy of AR, BRD4, and H3K27Ac in MR42D Cells in response to Enzalutamide [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147876 | GEO | 2021/06/22

REPOSITORIES: GEO

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Chromatin Occupancy of AR, BRD4, and H3K27Ac in MR42D Cells in response to Enzalutamide [ChIP-seq]

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

Expression data from LNCaP cells treated with DHT and enzalutamide

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

Chromatin Occupancy of AR, BRD4, and H3K27Ac in MR42D Cells in response to Enzalutamide [ATAC-seq]

Project description:In order to look at global chromatin accessibility in enzalutamide sensitive (V16D) and enzalutamide-resistant t-NEPC lines (MR42D), we treated these lines with enzalutamide or vehicle and performed an Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-seq). Hyperaccessible regions in V16D were associated with metabolic pathways, whereas hyperaccesible regions in MR42D were associated with neuronal pathways, indicating that the chromatin conformation in these enzalutamide resistant cells is conducive to transdifferentiation to a neuronal t-NEPC phenotype.

2021-06-22 | GSE147874 | GEO

LNCAP/AR and a LnCAP/AR subline (LREX') with acquired resistance to 2nd generation antiandrogens

Project description:The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Using the LnCaP/AR xenograft model, we identified induction of glucocorticoid receptor (GR) expression as a common feature of drug resistant tumors. From a resistant xenograft tumor, we derived a GR expressing resistant subline called LREX' which maintains the resistant phenotype. mRNA expression was used to characterize resistant tissues. LnCaP/AR cells were injected into castrate mice and tumors were established. Mice were then treated with vehicle (Con), 4 days of anti-androgen (ARN-509 10mgkg), or were maintained on anti-androgen (10mg/kg ARN-509 or enzalutamide) until emergence of resistance. Resistant tissues continued to be exposed to anti-androgen through time of harvest. LREX' (LnCaP/AR Resistant to Enzalutamide Xenograft Derived) was derived from an enzalutamide resistant xenograft and was re-injected into castrate mice undergoing continual treatment with enzalutamide. The GR probe on the Illumina array failed to detect GR expression. Therefore, GR expression as determined by qPCR is annotated separately. Of the 10 control tissues, 8 were analyzed twice (technical duplicates annotated as A and B).

2013-12-27 | E-GEOD-51873 | biostudies-arrayexpress

Identification of Radiosensitivity Gene Signatures Induced by Enzalutamide in Prostate cancer cells

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2019-07-01 | GSE126881 | GEO

RNA-seq profiling identifies Androgen Receptor-regulated genes in prostate cancer cells

Project description:The goal of this analysis is to profile AR-regulated genes, especially non-coding RNAs in three androgen sensitive prostate cancer cell lines, MDA-PCA-2B, LNCaP and VCaP. The two cell lines were serum-starved first, followed by dihydrotestosterone (DHT) stimulation or treated with Enzalutamide (AR inhibitor) without starvation. Transcriptome profiling was generated by RNA-sequencing from polyA-selected RNA. These experiments are followed by knock-down experiments of AR and ARlnc1 in MDA-PCA-2B, and also Enzalutamide (anti-androgen) treatment of LNCaP cells.

2018-02-21 | GSE110903 | GEO

Novel RORg inverse agonists do not modulate androgen receptor activity in prostate cancer

Project description:Work published by Wang et al. described pharmacological inhibition of RORg with an inverse agonist (SR2211) which led to a decrease in AR gene expression and a reduction in AR protein, which led to the loss of an AR gene expression signature. We have developed a novel, specific, RORg inverse agonist (AZ RORgi) and have studied its effects on the transcriptome of LNCAP cell lines following 24 & 48 hours of treatment. We compare this to SR2211 as well as Enzalutamide, an AR antagonist. We show that Enzalutamide and SR2211 primarily act via the androgen receptor, whereas AZ RORgi does not modulate gene expression in these cell lines.

2019-12-31 | E-MTAB-7294 | biostudies-arrayexpress

RET Kinase Inhibition in Neuroendocrine Prostate Cancer, part 1

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2020-05-29 | PXD012970 | Pride

RET Kinase Inhibition in Neuroendocrine Prostate Cancer, part 2

2020-05-29 | PXD012971 | Pride

Effect of MPC309 (AR-targeting Multivalent Peptoid Conjugate) treatment on gene expression in LNCaP-ABL cells (castration-resistant prostate cancer cell line) in comparison to Vehicle control and another AR ligand, Ethisterone (partial agonist): ChIP-Seq

Project description:To establish wehther the genes stimulated or inhibited by MPC309 are directly influenced by the AR, we conducted ChIP-seq of AR from LNCaP-abl cells that had been treated with vehicle (DMSO), MPC309, Backbone, DHT, or Enzalutamide overnight. Our results revealed a more pronounced AR presence in cells exposed to MPC309 and DHT as compared to control groups and those treated with enzalutamide, reinforcing the idea that MPC309 facilitates distinct AR interactions with chromatin. Genes linked with AR occupancy mirrored similar GO terms as those seen in RNA-seq experiments. Out of the 251 genes repressed by MPC309 compared to controls (vehicle and backbone), 246 (98%) had an AR binding site within 15 kb upstream or downstream of the gene promoter. Similarly, of the 405 genes stimulated by MPC309, 387 (96%) had an AR binding site within 15 kb of the gene promoter. These observations suggest that the gene regulation driven by MPC309 stems from AR interactions with chromatin, resulting in varying impacts on gene expression compared to DHT or enzalutamide, consequently inhibiting the growth of prostate cancer cells.

2023-07-11 | GSE236287 | GEO

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