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GATA2 up-regulation restores androgen receptor chromatin association and advances darolutamide resistance in prostate cancer

ABSTRACT: GATA2 up-regulation restores androgen receptor chromatin association and advances darolutamide resistance in prostate cancer

PROVIDER: PRJNA1049031 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27104110_1.fastq.gz	Fastqsanger.gz
	SRR27104110_2.fastq.gz	Fastqsanger.gz
	SRR27104111_1.fastq.gz	Fastqsanger.gz
	SRR27104111_2.fastq.gz	Fastqsanger.gz
	SRR27104112_1.fastq.gz	Fastqsanger.gz

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GATA2 up-regulation restores androgen receptor chromatin association and advances darolutamide resistance in prostate cancer

Project description:Darolutamide is an anti-androgen drug clinically used for prostate cancer therapy. Despite its efficacy, potential drug resistance poses significant challenges in the clinical setting. To better understand the molecular changes resulting from prolonged exposure to darolutamide, we developed a darolutamide-resistant model using LNCaP prostate cancer cells. Through ChIP-seq analysis, we found that a temporary treatment of cells with darolutamide effectively disrupts AR binding to chromatin. However, in darolutamide-resistant cells, the chromatin binding of AR is largely restored. By an integrative analysis of ChIP-seq and RNA-seq, we further identified GATA2, a pioneer factor for AR, substantially upregulated in darolutamide-resistant cells. GATA2 plays an essential role in promoting the proliferation of darolutamide-resistant cells and directly contributes to drug resistance. The ablation of GATA2 by siRNA abolished AR's recruitment to chromatin, leading to a significant reduction in gene expression regulated by AR in these resistant cells. Conversely, the overexpression of GATA2 in prostate cancer cells promoted cell proliferation and resistance to darolutamide. This study demonstrates the significance of GATA2 in the development of darolutamide resistance and suggests GATA2 as a promising therapeutic target to overcome this resistance.

2024-12-31 | GSE249437 | GEO

GATA2 upregulation restores androgen receptor chromatin association and advances darolutamide resistance in prostate cancer (RNA-Seq)

Project description:GATA2 upregulation restores androgen receptor chromatin association and advances darolutamide resistance in prostate cancer (RNA-Seq)

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GATA2 upregulation restores androgen receptor chromatin association and advances darolutamide resistance in prostate cancer (ChIP-Seq)

Project description:GATA2 upregulation restores androgen receptor chromatin association and advances darolutamide resistance in prostate cancer (ChIP-Seq)

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GATA2 upregulation restores androgen receptor chromatin association and advances darolutamide resistance in prostate cancer (RNA-Seq)

Project description:Darolutamide is the latest FDA-approved antiandrogen for the treatment of metastatic prostate cancer. Despite its efficacy in prolonging disease-free survival, drug resistance invariably develops. This study aims to understand the molecular mechanisms underlying darolutamide resistance and identify potential therapeutic targets for overcoming the resistance.

2024-12-31 | GSE249436 | GEO

GATA2 upregulation restores androgen receptor chromatin association and advances darolutamide resistance in prostate cancer (ChIP-Seq)

2024-12-31 | GSE249435 | GEO

Darolutamide antagonizes androgen signaling by blocking enhancer and super-enhancer activation [ChIP-seq]

Project description:The androgen receptor (AR) antagonist darolutamide has very recently been approved for the treatment of non-metastatic castration resistant prostate cancer (PCa). Here we determined the genome-wide effects of darolutamide on cis-acting regulatory elements involved in androgen signaling with a focus on enhancer and super-enhancer (SE) regions. Darolutamide strongly depleted the AR from regulatory elements and abolished the AR transcriptional signaling. Using two different androgen-dependent PCa cell lines we identified genomic-regions with different affinities for the AR in androgen-stimulated, androgen-depleted and darolutamide-antagonized conditions. Altogether, our findings demonstrate that darolutamide is a potent AR antagonist blocking genome-wide AR signaling and AR enhancer activation. Further, we show a dynamic AR cistrome and concomitant adapting chromatin environment to varying conditions and identified regions with high AR affinity in cell lines and tissue samples.

2020-04-10 | GSE148358 | GEO

Darolutamide antagonizes androgen signaling by blocking enhancer and super-enhancer activation [RNA-seq]

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Comparative proteomic and transcriptomic analysis of the impact of androgen stimulation and darolutamide inhibition on prostate cancer cells

Project description:Androgen receptor (AR) signaling is a major driver and therapy target in prostate cancer. Several inhibitors of AR function are approved for different stages of the disease and their impact on downstream gene transcription has been described. However, the ensuing effects of androgen and anti-androgens at the protein level are less well understood. Here, we focused on the AR inhibitor darolutamide which has recently been approved for non-metastatic castration-resistant prostate cancer. Here we determined the impact of darolutamide, a recently approved AR antagonist which significantly extends progression-free and overall survival in non-metastatic CRPC (31, 32), on the prostate cancer proteome. We first determined the direct binding between darolutamide and the AR in living prostate cancer cells in a label-free context using the cellular high throughput thermal shift assay (CETSA HT). We then generated comprehensive proteomic profiles of prostate cancer cells treated with androgen and darolutamide, and compared them with transcriptomic profiles. We found a generally high concordance between proteomic and transcriptomic data, both on the level of detected expressed genes and their protein products, as well as in terms of the corresponding biological programs. However there were cases where protein and gene expression levels were not regulated in parallel, suggesting an additional post-transcriptional regulation step controlling protein abundance to occur in several instances.

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GATA2 facilitates steroid receptor coactivator (SRC) recruitment to the androgen receptor (AR) complex

Project description:The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC), and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent (including constitutively active AR splice variants) mechanisms highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA2 as a regulator of AR signaling and a novel therapeutic target in PC. We demonstrate that GATA2 directly promotes AR expression (both full-length and splice variant), resulting in a strong positive correlation between GATA2 and AR expression in PC (cell lines and patient specimens). Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of AR (both full-length and splice variant). GATA2 co-localizes with AR and FOXA1 on chromatin to enhance recruitment of steroid receptor coactivators (SRCs) and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted for worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of AR (both full-length and splice variant) and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a “first-in-field” approach to target AR expression and function and improve outcomes in CRPC. LNCaP cells were transfected with control siRNA (3), GATA2 siRNA (3) or AR siRNA for 72 hours.

2015-01-21 | E-GEOD-63539 | biostudies-arrayexpress

GATA2 facilitates steroid receptor coactivator (SRC) recruitment to the androgen receptor (AR) complex

2015-01-21 | GSE63539 | GEO