Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA229499 | ENA |
REPOSITORIES: ENA
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Project description:Prostate carcinogenesis is associated with changes in androgen signaling from driving cellular differentiation to promoting oncogenic behaviors. RUNX2 binds the androgen receptor (AR), and ectopic expression of RUNX2 is linked to prostate cancer (PCa) progression. We therefore investigated genome-wide the influence of RUNX2 on androgen-induced gene expression and AR DNA binding in PCa cells. The predominant function of RUNX2 is to inhibit the androgen response, attributable in part to dissociation of AR from target genes such as the tumor suppressor NKX3-1. At a minority of AR target genes, however, AR activity persists in the presence of RUNX2. Some of these genes are co-operatively stimulated by androgen and RUNX2 signaling and are characterized by the presence of putative enhancers co-occupied by AR and RUNX2. Genes synergistically stimulated by AR and RUNX2 include the invasion-promoting transcription factor SNAI2. Indeed, co-activation of AR and RUNX2, but neither alone, stimulated PCa cell invasiveness, which was abolished by SNAI2 silencing. Accordingly, PCa biopsies most strongly stained for SNAI2 exhibit high nuclear expression of both RUNX2 and AR. The RUNX2-mediated locus-dependent modulation of AR activity in PCa opens a research avenue that may guide the development of novel diagnostic and therapeutic approaches to patient management. total RNA from C4-2B/Rx2dox cells was extracted in biological triplicates from four different conditions. Ethanol vehicle control, dox to induce RUNX2 expression, DHT to activate androgen receptor and DHT+dox combined.
2014-03-20 | E-GEOD-52627 | biostudies-arrayexpress
Project description:Prostate carcinogenesis is associated with changes in androgen signaling from driving cellular differentiation to promoting oncogenic behaviors. RUNX2 binds the androgen receptor (AR), and ectopic expression of RUNX2 is linked to prostate cancer (PCa) progression. We therefore investigated genome-wide the influence of RUNX2 on androgen-induced gene expression and AR DNA binding in PCa cells. The predominant function of RUNX2 is to inhibit the androgen response, attributable in part to dissociation of AR from target genes such as the tumor suppressor NKX3-1. At a minority of AR target genes, however, AR activity persists in the presence of RUNX2. Some of these genes are co-operatively stimulated by androgen and RUNX2 signaling and are characterized by the presence of putative enhancers co-occupied by AR and RUNX2. Genes synergistically stimulated by AR and RUNX2 include the invasion-promoting transcription factor SNAI2. Indeed, co-activation of AR and RUNX2, but neither alone, stimulated PCa cell invasiveness, which was abolished by SNAI2 silencing. Accordingly, PCa biopsies most strongly stained for SNAI2 exhibit high nuclear expression of both RUNX2 and AR. The RUNX2-mediated locus-dependent modulation of AR activity in PCa opens a research avenue that may guide the development of novel diagnostic and therapeutic approaches to patient management.
2014-03-20 | GSE52627 | GEO
Project description:Prostate cancer is driven by oncogenic transcription factor enhanceosomes comprising chromatin and epigenetic regulators. The lysine acetyltransferases p300 and CBP are key cofactors that activate enhancers through histone acetylation. Here, we identify p300/CBP-mediated multisite acetylation of the histone H2B N-terminus (H2BNTac) as a defining feature of oncogenic enhanceosomes in androgen receptor (AR)-positive prostate cancer. p300/CBP are essential for AR and ERG transcriptional activity, and their dual degradation eliminates H2BNTac and H3K27ac marks at hyperactive enhancers more effectively than targeting either paralog or bromodomains alone. Cytotoxicity profiling across >900 cell lines revealed that tumors with high H2BNTac, including AR-positive prostate cancer, are selectively dependent on p300/CBP. In preclinical models, systemic p300/CBP degradation inhibited tumor growth, synergized with AR antagonists, and showed no evident toxicity. These findings position H2BNTac as a key epigenetic marker of enhancer addiction and support dual p300/CBP degradation as a promising therapy for enhancer-driven cancers.
2025-07-28 | PXD065228 | Pride
Project description:Prostate cancer is driven by oncogenic transcription factor enhanceosomes comprising chromatin and epigenetic regulators. The lysine acetyltransferases p300 and CBP are key cofactors that activate enhancers through histone acetylation. Here, we identify p300/CBP-mediated multisite acetylation of the histone H2B N-terminus (H2BNTac) as a defining feature of oncogenic enhanceosomes in androgen receptor (AR)-positive prostate cancer. p300/CBP are essential for AR and ERG transcriptional activity, and their dual degradation eliminates H2BNTac and H3K27ac marks at hyperactive enhancers more effectively than targeting either paralog or bromodomains alone. Cytotoxicity profiling across >900 cell lines revealed that tumors with high H2BNTac, including AR-positive prostate cancer, are selectively dependent on p300/CBP. In preclinical models, systemic p300/CBP degradation inhibited tumor growth, synergized with AR antagonists, and showed no evident toxicity. These findings position H2BNTac as a key epigenetic marker of enhancer addiction and support dual p300/CBP degradation as a promising therapy for enhancer-driven cancers.
2025-07-28 | PXD065292 | Pride
Project description:Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 InhibitorsModulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors
| PRJNA659344 | ENA
Project description:The androgen/androgen receptor (AR) signaling drives prostate development and prostatic carcinogenesis, whereas loss of the zinc finger homeobox 3 (ZFHX3) transcription factor attenuates prostate development and promotes prostatic tumorigenesis. The androgen/AR signaling upregulates the transcription of ZFHX3 in prostate cancer cells. However, whether and how ZFHX3 is involved in the function of AR signaling in prostate cancer cells is unknown. In this study, we first carried out RNA-seq analysis in C4-2B prostate cancer cells to detect what genes and signaling pathways are caused by the deletion of ZFHX3. Gene set enrichment analysis (GSEA) revealed that among the top altered hallmark gene sets after ZFHX3 deletion, only the one for androgen response was decreased, whereas those for TNFα, interferon γ, and inflammatory response were enriched. For the 27 genes indicative AR activities, as defined in a previous study, expression levels for 18 of the 27 genes were significantly changed by ZFHX3 loss. Fifteen of these 18 genes were downregulated, including classical AR target genes KLK3, FKBP5, and TMPRSS2.
2025-07-09 | GSE288366 | GEO
Project description:To investigate the mechanisms of drug resistance and castration resistance in prostate cancer, we performed proteomic sequencing on androgen-dependent prostate cancer cells (LNCaP) and androgen-independent cells (AI) treated with enzalutamide.
2024-11-26 | PXD058261 |
Project description:Aberrant androgen receptor (AR)-mediated transcription is a critical driver in progression of human prostate cancer. It's known that different doses of androgens can elicit differential transcriptional and proliferative responses in prostate-tumor cells. Here, we set out to examine the androgenic regulation of glycoprotein expression in the membrane fraction of prostate-tumor cells that could serve as mediators or markers of androgen-induced proliferative responses observed in prostate-tumor cells. A bioanalytical workflow involving lectin-affinity chromatography and label-free quantitative mass spectrometry was used to identify androgen-sensitive glycomembrane protein expression associated with androgen-mediated proliferation. This study would facilitate the identification of surface membrane proteins involved in androgen-mediated proliferation and provide potential therapeutic targets in the detection treatment of proliferation prostate-tumors.
2022-03-01 | PXD002913 | Pride
Project description:The androgen receptor is considered as the key promoter of prostate cancer. It is a transcription factor that controls the transcription of hundreds of its target genes. In this project we focuses on how androgen receptor stimulation by the synthetic androgen R1881 can affect the proteome of peroxiosmes and the antioxidant enzymes in LNCaP cells.
2024-11-01 | PXD054374 | Pride
Project description:Genomic and transcriptomic alterations are insufficient to explain the variance in protein expression seen in cancer. Recent evidence has highlighted the role of N6-methyladenosine (m6A) in the regulation of mRNA expression, stability and translation, supporting a potential role for post-transcriptional regulation mediated by m6A in cancer. Here we explore prostate cancer as an exemplar cancer and generate the first prostate m6A maps, and further examined how low levels of N6-adenosine-methyltransferase (METTL3) associates with advanced prostate cancer and results in altered expression at the level of transcription, translation, and protein. In particular extracellular matrix proteins have a high number of m6A sites and show significant changes in expression with METTL3 knock-down. We also discovered the upregulation of a hepatocyte nuclear factor-driven gene signature that is associated with therapy resistance in prostate cancer. Significantly, METTL3 knock-down rendered the cells resistant to androgen receptor antagonists, implicating changes in m6A as a mechanism for therapy resistance in metastatic prostate cancer.
2021-06-07 | PXD022348 | Pride