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

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

PROVIDER: PRJNA624138 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11519200.fastq.gz	Fastqsanger.gz
	SRR11519300.fastq.gz	Fastqsanger.gz
	SRR11519201.fastq.gz	Fastqsanger.gz
	SRR11519301.fastq.gz	Fastqsanger.gz
	SRR11519202.fastq.gz	Fastqsanger.gz

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Darolutamide antagonizes androgen signaling by blocking enhancer and super-enhancer activation

Project description:Darolutamide antagonizes androgen signaling by blocking enhancer and super-enhancer activation

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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.

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

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

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

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Darolutamide antagonizes androgen signaling by blocking enhancer and super-enhancer activation.

Project description:Prostate cancer (PCa) is one of the most frequent tumor types in the male Western population. Early-stage PCa and late-stage PCa are dependent on androgen signaling, and inhibitors of the androgen receptor (AR) axis represent the standard therapy. Here, we studied in detail the global impact of darolutamide, a newly approved AR antagonist, on the transcriptome and AR-bound cistrome in two PCa cell models. Darolutamide strongly depleted the AR from gene regulatory regions and abolished AR-driven transcriptional signaling. Enhancer activation was blocked at the chromatin level as evaluated by H3K27 acetylation (H3K27ac), H3K4 monomethylation (H3K4me1), and FOXA1, MED1, and BRD4 binding. We identified genomic regions with high affinities for the AR in androgen-stimulated, but also in androgen-depleted conditions. A similar AR affinity pattern was observed in healthy and PCa tissue samples. High FOXA1, BRD4, H3K27ac, and H3K4me1 levels were found to mark regions showing AR binding in the hormone-depleted setting. Conversely, low FOXA1, BRD4, and H3K27ac levels were observed at regulatory sites that responded strongly to androgen stimulation, and AR interactions at these sites were blocked by darolutamide. Beside marked loss of AR occupancy, FOXA1 recruitment to chromatin was also clearly reduced after darolutamide treatment. We furthermore identified numerous androgen-regulated super-enhancers (SEs) that were associated with hallmark androgen and cell proliferation-associated gene sets. Importantly, these SEs are also active in PCa tissues and sensitive to darolutamide treatment in our models. Our findings demonstrate that darolutamide is a potent AR antagonist blocking genome-wide AR enhancer and SE activation, and downstream transcription. We also show the existence of a dynamic AR cistrome that depends on the androgen levels and on high AR affinity regions present in PCa cell lines and also in tissue samples.

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Darolutamide antagonizes androgen signaling by blocking enhancer and super-enhancer activation

Project description:This SuperSeries is composed of the SubSeries listed below.

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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.

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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)

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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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