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

ABSTRACT: 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)α, 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 ERα, 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58615 | GEO | 2014/06/19

SECONDARY ACCESSION(S): PRJNA253024

REPOSITORIES: GEO

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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

Homo sapiens

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

| PRJNA253024 | ENA

Assembly of methylated LSD1 and CHD1 drives AR-dependent transcription and translocation [ChIP-Seq]

Project description:The aim of the study is to identify AR target gens in LNCaP cells 5 samples corresponding to LSD1 K114me2 or CHD1 genome-binding in DHT-treated and control LNCaP cells. 6 samples corresponding to LSD1 K114me2 or CHD1 genome-binding in LNCaP cells knocked-down for LSD1 or CHD1 and treated with DHT.

2015-12-07 | E-GEOD-64528 | biostudies-arrayexpress

AR ChIP-seq with DHT induction and GSK treatment

Project description:The major pioneer factor activity of FOXA1 in PCa is to facilitate AR recruitment to androgen-regulated enhancers. Therefore, we hypothesized that the decreased FOXA1 binding and enhancer availability by LSD1 inhibition may result in the impairment of subsequent AR recruitment to enhancers. To globally test this hypothesis, we performed AR ChIP-seq in LNCaP cells treated with an LSD1 inhibitors. Consistent with previous reports, DHT treatment can dramatically induce AR binding to chromatin. Significantly, LSD1 inhibitor treatment in presence of DHT stimulation markedly decreased the total number of AR binding peaks and their intensity. We further assessed the impact of LSD1 inhibition on overall AR transcriptional output using RNA-seq data.

2019-09-29 | GSE114266 | GEO

Cistrome analyses of AR stimulated by 0.1 nM DHT in LNCaP stable cell line overexpressing AR [ChIP-Seq]

Project description:The molecular drivers for the AR signaling reprogramming in castration-resistant prostate cancer remain to be determined. In this study, we hypothesize that increased AR expression in conjunction with lower-level androgens, which is a typical condition in prostate cancer cells receiving androgen deprivation therapy, is a major driving force of the reprogramming. To test this, we used LNCaP model with inducible overexpression of AR to examine the acute effects of AR overexpression stimulated by low-dose DHT (0.1nM) on AR cistrome.

2022-11-21 | GSE211639 | GEO

Transcriptome analyses of AR stimulated by 0.1 nM or 10 nM DHT in LNCaP stable cell line overexpressing AR [RNA-Seq]

2022-11-21 | GSE211638 | GEO

Androgen receptor Serine 81 phosphorylation is coupled to AR-mediated transactivation and co-sustained by CDK1 and CDK9 in prostate cancer

Project description:We examine total AR verus pSer81-phosphorylated AR chromatin-binding profiling in DHT-treated LNCaP cells to address the molecular functions of pS81 on the chromatin, and demonstrate that S81 phosphorylation can be mediated by both CDK1 and CDK9 at basal and androgen-stimulated levels.

2021-02-05 | GSE166192 | GEO

AR regulated transcriptome in prostate cancer cells

Project description:It has been well established that the transcription factor androgen receptor (AR) is obligatory for prostate cancer (PCa) development and progression, but the precise role of the AR in these processes is still unclear. To dissect the role of AR in shaping the transcriptome of prostate cancer cells, RNA-seq data were obtained from AR-positive LNCaP cells treated with various regimens to manipulate endogenous AR signaling. LNCaP cells were cultured in normal medium containing fetal bovine serum (FBS) to represent an androgen-dependent (AD) growth state. To mimic the clinical androgen-deprivation-therapy (ADT) settings, cells were grown for 4 days in conditions of either depletion of androgen (i.e., medium containing charcoal:dextran stripped fetal bovine serum (CDSS)) or the presence of AR antagonist Enzalutamide (MDV3100, 10 μM) to represent androgen-independent (AI) growth states. Aside from the pharmaceutical modulations, we also utilized siRNA to knockdown AR. To examine the direct effects of AR signaling on gene transcription and splicing, cells were primed with CDSS for 3 days followed by treatment of 10nM dihydrotestosterone (DHT) for 8-9 hrs. Deep sequencing of rRNA-depleted total RNAs was performed in biological duplicates on abovementioned LNCaP cultures.

2020-03-04 | GSE114052 | GEO

ZR-75-1 microarray expression data

Project description:Testing the hormonal response of ZR-75-1 cells to estrogen, androgens, and a combination of both homones, with view determining the crosstalk between the transcriptional programs mediated by these hormones in breast cancer cells, and comparison with matched ChIP sequencing data for AR and ERalpha. Data analysis demonstrated reciprocal interference between 5α-dihydrotestosterone (DHT)- and estradiol (E2)-induced transcriptional programs. Specifically, regulation of 26% of E2 and 15% of DHT target genes was significantly affected by cotreatment with the other hormone, in the majority of cases (78-83%) antagonistically. Pathway analysis suggested that DHT co-treatment, for example, depleted E2-regulted pathways in cell survival and proliferation. Total RNA was extractd from luminal-like breast cancer ZR-75-1 cells in quadruplicate after treatment for 16h with 10nM of E2, DHT or E2+DHT.

2012-10-03 | E-GEOD-38132 | biostudies-arrayexpress

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

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