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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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236287 | GEO | 2023/07/11

REPOSITORIES: GEO

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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): ATAC-Seq

Project description:We conducted ATAC-seq on LNCaP-abl cells treated overnight with either vehicle (DMSO), MPC309, Backbone, DHT or Enzalutamide to reveal areas of accessible chromatin. Our results indicated that the vast majority of peaks (>46,000) were shared among all groups. Notwithstanding, MPC309 incited some chromatin restructuring, as evidenced by the unique 8,750 open chromatin sites seen in cells treated with MPC309 as opposed to those treated with the vehicle. Analysis of transcription factor (TF) binding-motifs around regions of chromatin exclusively open in MPC309-treated cells exposed NR-binding motifs (GRE, PRE, ARE, AR-half sites). This indicates the potential for MPC309-bound AR to interact with chromatin at AR-specific locations.

2023-07-11 | GSE236288 | GEO

Project description:Prostate cancers evolve to resist androgen receptor (AR) pathway inhibitors, such as enzalutamide, leading to castration resistance due to sustained AR expression and function. In response, we have designed a novel strategy to regulate the AR and suppress castration-resistant prostate cancer (CRPC) by employing multivalent peptoid conjugates (MPCs). These conjugates comprise multiple copies of the AR-targeting ligand ethisterone attached to a peptidomimetic framework. To pinpoint the genes and pathways impacted by MPC309, we performed RNA-sequencing on LNCaP-abl cells, which were treated overnight with various agents: vehicle (DMSO), peptoid backbone, MPC309, dihydrotestosterone (an AR activator), or enzalutamide (an AR inhibitor commonly used clinically). Our findings revealed unique gene expression patterns (transcriptomes) in cells exposed to each compound, indicating that MPC309 may be a new AR ligand influencing the AR transcriptional response.

2023-07-11 | GSE236286 | 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 [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

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

MDA-PCa-2b cells, Control vs. ARlnc1 knockdown, AR-regulated gene signature generated by DHT treatment

Project description:(1) Transcription profiling of MDA-PCa-2b cells comparing ARlnc1 knockdown treated cells with control cells. Two methods were used to knockdown ARlnc1: siRNA or ASO. (2) Transcription profiling of MDA-PCa-2b cells comparing dihydrotestosterone (DHT) stimulated cells with vehicle treated cells. The goal is to determine AR-regulated gene expression signature in MDA-PCa-2b cells.

2018-02-16 | GSE95000 | GEO

Expression data from LNCaP cells treated with DHT and enzalutamide

2013-04-01 | GSE44905 | GEO

Targeting androgen receptor phase separation to overcome antiandrogen resistance mediated by "pharmacological condensates"

Project description:Analyze the transcriptomic changes of LNCaP upon DMSO, DHT, Enzalutamide(ENZ), ET516 treatment. The DHT treatment induced robust androgen receptor (AR) signaling up-regulation, wheras ENZ and ET516 can significantly restore DHT-induced AR signaling changes.

2021-10-05 | GSE185223 | GEO

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

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

DHT-AR, E2-AR and R5020-AR target gene profiles in LNCaP

Project description:We previously encountered regulatory processes where dihydrotestosterone (DHT) exerted its inhibitory effect on parathyroid hormone-related protein (PTHrP) gene repression through the estrogen receptor (ER)M-NM-1, but not the androgen receptor (AR) in breast cancer MCF-7 cells. Here, we investigated whether such an aberrant ligand-nuclear receptor (NR) interaction is present in prostate cancer LNCaP cells. First, we confirmed that LNCaP cells expressed a functional AR and at negligible levels of ERM-NM-1, and progesterone receptors. Both suppression of PTHrP and activation of the PSA genes were observed after treatment of E2, DHT and R5020. Consistent with the previous notion that the AR in LNCaP cells lost the ligand specificity due to a mutation AR (Thr-Ala877), our study using siRNA targeting each NR revealed that the AR, but not the other NRs, monopolized the role as the mediator of shared hormone-dependent regulation. These results were invariably associated with nuclear translocation of this mutant AR. Microarray of the genes regulated by either DHT, E2 or R5020 downstream of the AR (Thr-Ala877) revealed that more than half genes overlapped in LNCaP cells. Noticeably, AR (wild-type, wt) and AR (Thr-Ala877) were equally responsible for the E2-AR interactions. Fluorescent microscopic experiments demonstrated that both EGFP-AR (wt) and EGFP-AR (Thr-Ala877) were exclusively localized within the nucleus after E2 or DHT treatment. Further, a promoter assay revealed that breast cancer MCF-7 and Rv22 cells also exhibited such an aberrant E2-AR (wt) signaling. We postulate entangled interactions between the AR (wt) and E2 in a certain hormone-sensitive cancer cells. Total RNAs from the LNCaP cells transfected with control siRNA (siCT) or siRNA for AR (siAR) transfected LNCaP cells before 24 hr followed by exposed to 10-7M of DHT, E2 or R5020 exposure for another 24 h, respectively, were used.

2014-06-19 | E-GEOD-58615 | biostudies-arrayexpress

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