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A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer
Open accessAbstract
Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide. Epigenetic data generated in localized prostate tumors and benign specimens support the notion that this region is a developmental enhancer. Collectively, these observations underscore the importance of epigenomic profiling in primary specimens and the value of deploying genome editing to functionally characterize noncoding elements. More broadly, this work identifies a therapeutic vulnerability for targeting the AR and emphasizes the importance of regulatory elements as highly recurrent oncogenic drivers.
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“We and other groups have identified tumor alterations that reactivate AR signaling during treatment with an ARSI2,22–29.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [24]
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“These mechanisms of resistance include AR gene amplification22,23, AR enhancer amplification2,24,25, AR mutation26, AR genomic structural rearrangements27, AR splice variants28 and polymorphisms in androgen metabolism genes29.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [24]
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Metadata
- Authors
- Takeda, D. Y., Spisák, S., Seo, J.-H., Bell, C., O’Connor, E., Korthauer, K., Ribli, D., Csabai, I., Solymosi, N., Szállási, Z., Stillman, D. R., Cejas, P., Qiu, X., Long, H. W., Tisza, V., Nuzzo, P. V., Rohanizadegan, M., Pomerantz, M. M., Hahn, W. C., & Freedman, M. L.
- Affiliations
- Broad Institute (US)
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- Eötvös Loránd University (HU)
- University of Veterinary Medicine (HU)
- Semmelweis University (HU)
- Boston Children's Hospital (US)
- Corresponding author
- Freedman, Matthew L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 174
- Issue
- 2
- Pages
- 422-432.e13
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6046260
- OpenAlex
- W2808687910
- Cited by
- 317
- References
- 55
- Citations by year
- 2026: 14 · 2025: 31 · 2024: 44 · 2023: 47 · 2022: 41 · 2021: 54 · 2020: 44 · 2019: 32 · 2018: 10
- FWCI
- 26.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Prostate Cancer Foundation Challenge Award
- NIH (R01GM107427, R01CA193910, K08CA218530, R01HG005220, U01 CA176058)
- National Research, Development and Innovation Fund of Hungary Project (FIEK_16-1-2016-0005)
- Novo Nordisk Foundation Interdisciplinary Synergy Programme (NNF15OC0016584)
- European Social Fund (EFOP-3.6.3-VEKOP-16-2017-00005)
- Breast Cancer Research Foundation (BCRF-17-156)
- H.L. Snyder Medical Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- androgen receptor, advanced prostate cancer, treatment resistance, enzalutamide resistance, non-coding regulatory elements, genome editing, epigenetic profiling, oncogenic drivers
- MeSH terms
- Gene Editing, Acetylation, Adult, Aged, Antineoplastic Agents, Benzamides, Cell Survival, Enhancer Elements, Genetic, Histones, Humans, Male, Middle Aged, Neoplasm Metastasis, Nitriles, Phenylthiohydantoin, Receptors, Androgen, DNA Methylation, Cell Line, Tumor, CRISPR-Cas Systems, Prostatic Neoplasms, Castration-Resistant
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