E-MTAB-5102
Ontology highlight
ABSTRACT:
PROVIDER: E-MTAB-5102 | ExpressionAtlas | 2025-01-23
REPOSITORIES: ExpressionAtlas
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| E-MTAB-5102-analysis-methods.tsv | Tabular | |||
| E-MTAB-5102-atlasExperimentSummary.Rdata | Rdata | |||
| E-MTAB-5102-configuration.xml | Xml | |||
| E-MTAB-5102-percentile-ranks.tsv | Tabular | |||
| E-MTAB-5102.condensed-sdrf.tsv | Tabular |
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Project description:Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Prior work has focused on targeting AR directly; however, the identification and targeting of co-activators of AR signaling remains an underexplored area. Here we demonstrate that the MLL (mixed-lineage leukemia) complex, a well-known contributor in MLL-fusion-positive leukemia, acts as a co-activator of AR signaling. AR interacts with the MLL complex via its subunit, menin. Small molecule inhibition of the menin-MLL interaction blocks AR signaling and inhibits tumor growth in vivo. Furthermore, we find that menin is up-regulated in CRPC and high expression correlates with poor overall survival. Our study identifies the MLL complex as a co-activator of AR that can be targeted in advanced prostate cancer. ASH2L / Menin / MLL1 were knocked down using shRNA /siRNA in two prostate cancer cell lines, VCaP and LNCaP.
2015-03-02 | E-GEOD-60836 | biostudies-arrayexpress
Project description:Transcription factors are among the most attractive therapeutic targets but are considered largely undruggable. Here we provide evidence that small molecule-mediated partitioning of the androgen receptor, an oncogenic transcription factor, into phase-separated condensates has therapeutic effect in prostate cancer. We show that the phase separation capacity of the androgen receptor is driven by aromatic residues and short unstable helices in its intrinsically disordered activation domain. Based on this knowledge, we developed tool compounds that covalently attach aromatic moieties to cysteines in the receptors’ activation domain. The compounds enhanced partitioning of the receptor into condensates, facilitated degradation of the receptor, inhibited androgen receptor-dependent transcriptional programs, and had antitumorigenic effect in mouse models of prostate cancer and castration resistant prostate cancer. These results establish a generalizable framework to target the phase-separation capacity of intrinsically disordered regions in oncogenic transcription factors and other disease-associated proteins with therapeutic intent.
2023-07-31 | GSE232849 | GEO
Project description:Transcription factors are among the most attractive therapeutic targets but are considered largely undruggable. Here we provide evidence that small molecule-mediated partitioning of the androgen receptor, an oncogenic transcription factor, into phase-separated condensates has therapeutic effect in prostate cancer. We show that the phase separation capacity of the androgen receptor is driven by aromatic residues and short unstable helices in its intrinsically disordered activation domain. Based on this knowledge, we developed tool compounds that covalently attach aromatic moieties to cysteines in the receptors’ activation domain. The compounds enhanced partitioning of the receptor into condensates, facilitated degradation of the receptor, inhibited androgen receptor-dependent transcriptional programs, and had antitumorigenic effect in mouse models of prostate cancer and castration resistant prostate cancer. These results establish a generalizable framework to target the phase-separation capacity of intrinsically disordered regions in oncogenic transcription factors and other disease-associated proteins with therapeutic intent.
2023-06-24 | GSE206853 | GEO
Project description:Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Prior work has focused on targeting AR directly; however, the identification and targeting of co-activators of AR signaling remains an underexplored area. Here we demonstrate that the MLL (mixed-lineage leukemia) complex, a well-known contributor in MLL-fusion-positive leukemia, acts as a co-activator of AR signaling. AR interacts with the MLL complex via its subunit, menin. Small molecule inhibition of the menin-MLL interaction blocks AR signaling and inhibits tumor growth in vivo. Furthermore, we find that menin is up-regulated in CRPC and high expression correlates with poor overall survival. Our study identifies the MLL complex as a co-activator of AR that can be targeted in advanced prostate cancer.
2015-03-02 | GSE60836 | GEO
Project description:Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. Here, we find that genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and anti-tumor immunity via recruitment of cytotoxic T-cells, ultimately impeding tumor progression. Our findings reveal a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.
2024-11-04 | GSE277063 | GEO
Project description:Metastatic prostate cancer is commonly localized in bone and treated with androgen ablation, which is initially highly effective, but eventually results in resistant cancer cells. The decreased dependence on androgen is associated with activation of the androgen receptor (AR) via other growth factor receptor pathways. The current study analyzed global gene expression in bone from castrated and sham operated C57BL/6 mice to identify factors that may be responsible for androgen signaling. Androgen suppression by castration increased the expression of 159 genes with insulin-like growth factor binding protein 5 (IGFBP5) being the most consistently increased. IGFBP5 protein was detected by immune histochemistry in osteoblasts, bone marrow stromal cells and endothelial cells. In vitro treatment of marrow stromal cells with charcoal-stripped serum increased IGFBP5 mRNA expression approximately 25-fold and was reversed by androgen supplementation. Endogenous IGFBP5 was incorporated into extracellular matrix. In addition, treatment of extracellular matrices with exogenous IGFBP5 and IGF-1 or IGF-2 enhanced the growth of immortalized human prostate cells. These results suggest that androgen ablative therapy may increase IGFBP5 in the marrow microenvironment, thereby providing support for the development of therapy resistance prostate cancer cells. Keywords: Bone Marrow Environment, Androgen Suppression, IGFBP5, prostate cancer
2007-06-01 | GSE5776 | GEO
Project description:Metastatic prostate cancer is commonly localized in bone and treated with androgen ablation, which is initially highly effective, but eventually results in resistant cancer cells. The decreased dependence on androgen is associated with activation of the androgen receptor (AR) via other growth factor receptor pathways. The current study analyzed global gene expression in bone from castrated and sham operated C57BL/6 mice to identify factors that may be responsible for androgen signaling. Androgen suppression by castration increased the expression of 159 genes with insulin-like growth factor binding protein 5 (IGFBP5) being the most consistently increased. IGFBP5 protein was detected by immune histochemistry in osteoblasts, bone marrow stromal cells and endothelial cells. In vitro treatment of marrow stromal cells with charcoal-stripped serum increased IGFBP5 mRNA expression approximately 25-fold and was reversed by androgen supplementation. Endogenous IGFBP5 was incorporated into extracellular matrix. In addition, treatment of extracellular matrices with exogenous IGFBP5 and IGF-1 or IGF-2 enhanced the growth of immortalized human prostate cells. These results suggest that androgen ablative therapy may increase IGFBP5 in the marrow microenvironment, thereby providing support for the development of therapy resistance prostate cancer cells. Keywords: Bone Marrow Environment, Androgen Suppression, IGFBP5, prostate cancer
2007-06-01 | GSE5775 | GEO
Project description:The androgen receptor (AR) is a mediator of both androgen-dependent and castration- resistant prostate cancers. Identification of cellular factors affecting AR transcriptional activity could in principle yield new targets that reduce AR activity and combat prostate cancer, yet a comprehensive analysis of the genes required for AR-dependent transcriptional activity has not been determined. Using an unbiased genetic approach that takes advantage of the evolutionary conservation of AR signaling, we have conducted a genome-wide RNAi screen in Drosophila cells for genes required for AR transcriptional activity and applied the results to human prostate cancer cells. We identified 45 AR-regulators, which include known pathway components and genes with functions not previously linked to AR regulation, such as HIPK2 (a protein kinase) and MED19 (a subunit of the Mediator complex). Depletion of HIPK2 and MED19 in human prostate cancer cells decreased AR target gene expression and, importantly, reduced the proliferation of androgen-dependent and castration-resistant prostate cancer cells. We also systematically analyzed additional Mediator subunits and uncovered a small subset of Mediator subunits that interpret AR signaling and affect AR-dependent transcription and prostate cancer cell proliferation. Importantly, targeting of HIPK2 by an FDA approved kinase inhibitor phenocopied the effect of depletion by RNAi and reduced the growth of AR-positive, but not AR negative, treatment-resistant prostate cancer cells. Thus, our screen has yielded new AR regulators including drugable targets that reduce the proliferation of castration-resistant prostate cancer cells. HIPK2 and MED19 were identified via a genome-wide RNAi screen as new androgen receptor (AR) reulators. Our goal in performing this microarray was to identify the gene regulated by HIPK2 and MED19 in a late stage prostate cancer cell line (LNCaP-abl), and to see what genes are in common with known genes to be regulated by AR, and what genes are unique to HIPK2 or MED19. Knockdown of HIPK2 and MED19 was tested in LNCaP-abl cells against control. Each was performed in duplicates. Six samples were analyzed
2013-01-30 | E-GEOD-43881 | biostudies-arrayexpress
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 patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance occurs when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or when constitutively active splice variants lacking the androgen binding domain entirely (e.g. ARV7) is expressed. In this study, we are reporting the discovery of novel AR-NTD covalent inhibitor 1‐chloro‐3‐[(5‐([(2S)‐3‐chloro‐2‐hydroxypropyl]amino)naphthalen‐1‐yl)amino]propan‐2‐ol (VPC-220010) targeting the AR-N-terminal Domain (AR-NTD). VPC-220010 inhibits AR-mediated transcription of full length and truncated variant ARV7, downregulates AR response genes, and selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines. We show that VPC-220010 disrupts interactions between AR and its known coactivators and interactors, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule AR-NTD inhibitor for the treatment of CRPC.
2021-07-28 | GSE173331 | GEO