A Gain-of-Function Mutation in DHT Synthesis in Castration-Resistant Prostate Cancer
Open accessAbstract
Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation that leads to a gain-of-function in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3βHSD1 is a valid target for the treatment of CRPC.
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Tumor alterations that reactivate AR signaling during treatment with an ARSI have been identified.
“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 [29]
The Results section reports selection of the HSD3B1(1245C) mutation in abiraterone-treated xenograft tumors and shows that its protein product amplifies androgen-regulated gene expression in a separate model. The Discussion says this suggests a mechanism of abiraterone resistance, but notes that its contribution to clinical resistance remains undetermined; the paper does not directly show AR signaling being reactivated during ARSI treatment. (LLM, conf=0.83)
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“We and other groups have identified tumor alterations that reactivate AR signaling during treatment with an ARSI 2,22–29 .”
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- Authors
- Chang, K.-H., Li, R., Kuri, B., Lotan, Y., Roehrborn, C. G., Liu, J., Vessella, R., Nelson, P. S., Kapur, P., Guo, X., Mirzaei, H., Auchus, R. J., & Sharifi, N.
- Affiliations
- Cleveland Clinic (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- The University of Texas Southwestern Medical Center (US)
- University of Michigan (US)
- University of Washington (US)
- Corresponding author
- Sharifi, Nima
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 154
- Issue
- 5
- Pages
- 1074-1084
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3931012
- OpenAlex
- W2100965400
- Cited by
- 312
- References
- 40
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 20 · 2023: 23 · 2022: 21 · 2021: 29 · 2020: 24 · 2019: 21 · 2018: 27 · 2017: 32 · 2016: 24 · 2015: 30 · 2014: 31 · 2013: 4
- FWCI
- 24.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (P01CA085859, PC093509, L30 CA135719, R01CA168899, P01CA163227, P50CA097186, R01CA172382, P01CA85859)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- castration-resistant prostate cancer, gain-of-function mutations, androgen receptor, dehydroepiandrosterone, enzyme stability, ubiquitination, androgen production, therapeutic target
- MeSH terms
- Androgens, Animals, Humans, Male, Prostatic Neoplasms, Dihydrotestosterone, 3-Hydroxysteroid Dehydrogenases, Gene Expression Regulation, Neoplastic, Mice, Ubiquitination, Proteolysis
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