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Darolutamide antagonizes androgen signaling by blocking enhancer and super‐enhancer activation
- Source :
- Molecular Oncology, Vol 14, Iss 9, Pp 2022-2039 (2020), Molecular Oncology
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
Abstract
- 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.<br />Schematic model showing how darolutamide blocks androgen (R1881)‐mediated AR signaling by inhibiting the function of normal enhancers and super‐enhancers, and impairing downstream gene transcription.
- Subjects :
- 0301 basic medicine
Hepatocyte Nuclear Factor 3-alpha
Male
Cancer Research
Transcription, Genetic
medicine.drug_class
Population
urologic and male genital diseases
lcsh:RC254-282
03 medical and health sciences
Prostate cancer
0302 clinical medicine
Cell Line, Tumor
androgen receptor
Genetics
medicine
Humans
Enhancer
education
Research Articles
education.field_of_study
Chemistry
Genome, Human
histone acetylation
Prostatic Neoplasms
super‐enhancer
General Medicine
medicine.disease
Androgen
cistrome
prostate cancer
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Chromatin
Cell biology
Androgen receptor
Gene Expression Regulation, Neoplastic
030104 developmental biology
Enhancer Elements, Genetic
Oncology
Cistrome
Receptors, Androgen
030220 oncology & carcinogenesis
Androgens
Molecular Medicine
Pyrazoles
FOXA1
Signal Transduction
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 15747891 and 18780261
- Volume :
- 14
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Molecular Oncology
- Accession number :
- edsair.doi.dedup.....6e299da73783c4e3c52e117f0324fd40