ArticleMolecular oncology2020
Darolutamide antagonizes androgen signaling by blocking enhancer and super-enhancer activation.
Article in Molecular oncology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
- Safety profile of darolutamide versus placebo: a systematic review and meta-analysis.Prostate cancer and prostatic diseases · 2024Pooled it
- Targeting the Androgen Receptor and Associated Cofactors in Prostate Cancer: Novel Approaches and Future Perspectives.International journal of molecular sciences · 2026Review
- Genome-wide chromatin profiling reveals a nonlimiting role for RXR in macrophage-like cells stimulated with multiple nuclear receptor agonists.The Journal of biological chemistry · 2026Article
- Induction of cellular senescence by androgen receptor agonist or antagonist is mediated via two novel common DYRK1A-DREAM and cyclin G2 signaling pathways in castration-resistant prostate cancer.Journal of advanced research · 2026Article
- Super-enhancers mediates SLC7A11 via FOXA1 to regulate disulfidptosis in prostate cancer.Cell death & disease · 2025Article
- Targeting RPS6KC1 to overcome enzalutamide resistance in prostate cancer.Biomarker research · 2025Article
- Functional circuits of LYL1 controlled by supraphysiological androgen in prostate cancer cells to regulate cell senescence.Cell communication and signaling : CCS · 2024Article
- Super-Enhancers and Their Parts: From Prediction Efforts to Pathognomonic Status.International journal of molecular sciences · 2024Review
- Loss of feedback regulation between FAM3B and androgen receptor driving prostate cancer progression.Journal of the National Cancer Institute · 2024Article
- Metabolic reprogramming directed by super-enhancers in tumors: An emerging landscape.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Review
- Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis.Molecular oncology · 2024Article
- Targeting super-enhancer activity for colorectal cancer therapy.American journal of translational research · 2024Review
- Article
- The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer.The Journal of clinical investigation · 2023Article
- Super-enhancers complexes zoom in transcription in cancer.Journal of experimental & clinical cancer research : CR · 2023Review
- LSD1 Inhibition Disrupts Super-Enhancer-Driven Oncogenic Transcriptional Programs in Castration-Resistant Prostate Cancer.Cancer research · 2023Article
- Comparative Proteomic and Transcriptomic Analysis of the Impact of Androgen Stimulation and Darolutamide Inhibition.Cancers · 2022Article
- Androgen receptor-mediated transcriptional repression targets cell plasticity in prostate cancer.Molecular oncology · 2022Article
- From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer.International journal of molecular sciences · 2022Review
- The emerging potentials of lncRNA DRAIC in human cancers.Frontiers in oncology · 2022Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.