Polycomb-mediated deactivation of AR-feedback loop leads to castration-resistant prostate cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA315571 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3234480.fastq.gz | Fastqsanger.gz | |||
| SRR3234481.fastq.gz | Fastqsanger.gz | |||
| SRR3234479.fastq.gz | Fastqsanger.gz |
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Project description:Castration-resistant prostate cancer (CRPC) is a lethal disease, often characterized by aberrant androgen receptor (AR) activation independently of androgen. We have previously reported that AR can directly repress the expression of many target genes, one of which is NOV/CCN3. Here we show that NOV, primarily localized in the cytoplasm, physically interacts with AR at its Nterminus and sequesters AR and AR variants in the cytoplasm, thereby reducing AR chromatintargeting. This negative feedback loop, however, is disrupted in CRPC due to epigenetic silencing of NOV by the Polycomb group protein EZH2, rendering AR transcriptional activities and drug-resistant prostate cancer progression. Our findings thus suggest a working model wherein AR-repressed genes critically prevent CRPC through negative feedback loops inhibiting AR signaling.
2017-02-19 | GSE79357 | GEO
Project description:Castration-resistant prostate cancer (CRPC) is a lethal disease, often characterized by aberrant androgen receptor (AR) activation independently of androgen. We have previously reported that AR can directly repress the expression of many target genes, one of which is NOV/CCN3. Here we show that NOV, primarily localized in the cytoplasm, physically interacts with AR at its Nterminus and sequesters AR and AR variants in the cytoplasm, thereby reducing AR chromatintargeting. This negative feedback loop, however, is disrupted in CRPC due to epigenetic silencing of NOV by the Polycomb group protein EZH2, rendering AR transcriptional activities and drug-resistant prostate cancer progression. Our findings thus suggest a working model wherein AR-repressed genes critically prevent CRPC through negative feedback loops inhibiting AR signaling.
2017-02-19 | GSE79356 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-02-19 | GSE79358 | GEO
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
Project description:Prostate cancer is the most common, lethal malignancy in men. Although androgen withdrawal therapies are used to treat advanced disease, progression to a castration-resistant, end-stage is the usual outcome. In this study, the tested hypothesis was that the androgen receptor remains essential for the growth and viability of castration-resistant disease. Knocking down the androgen receptor in well-established tumors grown in castrated mice caused growth arrest, decreased serum PSA, and frequently regression and total eradication of tumors. Growth control of castration-resistant tumors appeared to be linked to the extent of androgen receptor knockdown, which triggers upregulation of many genes involved in apoptosis, cell cycle arrest, and inhibition of tumorigenesis and protein synthesis. Our findings provide proof of principle that in vivo knockdown of the androgen receptor is a viable therapeutic strategy to control and possibly eradicate prostate cancers that have progressed to the lethal castration-resistant state. C4-2 human prostate cancer cells stably expressing a tetracycline-inducible AR-targeted short hairpin RNA (shRNA) or scrambled shRNA were generated. These two cell lines were incubated in the absence of androgens with or without doxycycline hyclase (DOX). Comparison analysis of the gene expression profiles of C4-2 cells stably expressing AR shRNA + DOX and control cells (AR shRNA - DOX and scrambled shRNA ± DOX) was conducted to identify differentially regulated genes due to AR knockdown after normalization and data filtering. Genes were considered to be significantly different if the expression in the induced AR shRNA + DOX cells was at least 1.7-fold greater or 1.7-fold less than that seen in the control cells, with P< 0.05.
2010-06-23 | E-GEOD-13332 | biostudies-arrayexpress
Project description:Castration-resistant PCa (CRPC) remains androgen receptor (AR) dependent. There are multiple mechanisms for reactivation of AR including expression of the constitutively active AR splice variant, AR-V7 (AR3). Earlier studies suggest that though the variants regulate many of the same genes as AR, they also have unique targets. Another argument is that the variant is a “weak” AR without unique targets. We have used an LN95 cell line that endogenously expresses AR and a low level of AR-V7 to compare the activities of the isoforms and to determine whether there is differential regulation of target genes. The transcriptomes for AR and AR-V7 were identified using RNA-Seq.
2021-12-31 | GSE184676 | GEO
Project description:Molecular mechanisms underlying resistance to androgen deprivation therapy (ADT) and, in particular, to antiandrogen Enzalutamide, in treating castration-resistant prostate cancer (CRPC), remain incompletely understood. Through screening >120 CRPC patient samples, we observed 3 expression patterns of androgen receptor (AR) protein: primarily nuclear (nuc-AR), mixed nuclear/cytoplasmic expression (nuc/cyto-AR), and low/no expression (AR-/lo). Xenograft CRPC modeling in 4 models (i.e., LNCaP, VCaP, LAPC4, and LAPC9) recapitulated the 3 AR expression patterns in castration-resistant tumors developed from parental androgen-dependent tumors. Strikingly, although the 3 CRPC models that retained AR expression (LNCaP, VCaP, and LAPC4) responded, to different levels and in different kinetics, to Enzalutamide, the AR-/lo LAPC9 CRPC was completely refractory to Enzalutamide. By combining whole-genome RNA-Seq and biochemical analyses together with experimental combinatorial therapy in the LNCaP and LAPC9 models, we identified BCL-2 as a critical therapeutic target in both AR+/hi and AR-/lo, Enzalutamide-resistant CRPC models.
2018-08-01 | GSE88752 | GEO
Project description:The purpose of this study was to characterize the downstream transcriptomic effects of ARVib-mediated degradation of AR/AR-V7, particularly in attenuating AR/AR-V7 target gene expression in prostate cancer cells. Towards this goal, next-generation sequencing (NGS)-based gene expression profiling (RNA-Sequencing; RNA-Seq) was performed on castration-resistant prostate cancer (CRPC) C4-2B MDVR cells that were treated with vehicle control or one of the AR/AR-V7 inhibitors (ARVib), ARVib-7 or ARVib-31.
2021-08-22 | GSE158556 | GEO
Project description:This study aimed at exploring how would the novel AR N-terminal inhibitor affect the androgen receptor (AR) transcriptome, especially a subset of genes that are uniquely upregulated by AR-V7 in castration resistant prostate cancer cells. We performed next-generation sequencing-based gene expression profiling (RNA-sequencing) on the castration-resistant prostate cancer celll line LNCaP-95. LNCaP-95 expresses high level of endogeneous AR-V7, and also acquired an adaptive shift towards AR-V7-mediated AR signaling activity. Beside regulating the transcription of a subset of canonical wildtype AR genes, AR-V7 also mediates a distinct transcriptional program that is independent of wildtype AR in LNCaP-95. In this experiment, LNCaP-95 cells were treated with vehicle control or the AR-N terminal inhibitor SC912. The subsequent AR transcriptomic change following compound treatment, especially the AR-V7 unique genes were assessed by RNA-seq.
2024-04-30 | GSE253122 | GEO
Project description:Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for invasive tumors. However, despite initial remission, the cancer will inevitably recur. The present study was set to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions Microarray technology was used to analyze differences in gene expression between androgen-responsive and hormone-refractory prostate cancer cell lines. As model system, we used the androgen-responsive PC346C cells and its castration-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2. These sublines were derived from the parental PC346C by long-term androgen ablation (PC346DCC), supplemented with the antiandrogen hydroxyflutamide (PC346Flu1 and PC346Flu2). Previous studies revealed distinct AR modifications in all three castration-resistant sublines: AR overexpression (PC346Flu1), AR down-regulation (PC346DCC) and T877A AR mutation (PC346Flu2). Each of the hormone-refractory sublines were cultured in their respective selection medium (steroid-stripped medium for PC346DCC, supplemented with 1 mM OH-Flutamide for PC346Flu1 and Flu2) and hybridized on the microarrays, together with the parental androgen-responsive PC346C (cultured in complete medium supplemented with 0.1 nM R1881). To account for the biological variability and dye-preferential binding to oligonucleotides on the microarray, four replicate arrays were performed per cell line, using two independent cell passages in dye-swap.
2010-10-21 | E-GEOD-21596 | biostudies-arrayexpress