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Updated: May 22, 2025
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
Ketogenesis instigates immune suppression in enzalutamide resistant prostate cancer via OTUD7B β-hydroxybutyrylation
Haoran Jiang1, Yuan Zeng2, Weiqiang Ning3
1Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; Institute of Urology, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; Zhejiang Key Laboratory of Critical Care Medicine,Wenzhou, 325000,Zhejiang China; Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, Zhejiang, China; Key Laboratory of Novel Nuclide Technologies on Precision Diagnosis and Treatment & Clinical Transformation of Wenzhou City, Wenzhou, 325035, Zhejiang, China; Department of Radiation Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
Abstract:
Next-generation androgen receptor inhibitors are the primary treatment for metastatic prostate cancer. Unfortunately, the majority of patients rapidly develop resistance. Resistance to enzalutamide has been linked to the emergence of an immunosuppressive tumor, although the underlying mechanisms remain poorly understood. In this study, we observed a marked overexpression of enzymes involved in the ketogenic pathway in enzalutamide-induced castration-resistant prostate cancer, which contributed to immune desertification and resistance to immunotherapy. Mechanistically, upregulation of the ketogenic pathway led to the accumulation of β-hydroxybutyrate, which promoted β-hydroxybutyrylation of the cell cycle-regulated deubiquitinase OTUD7B at lysine 511. This modification impaired the degradation of APC/C substrates, resulting in a subsequent reduction in cytoplasmic double-stranded DNA accumulation, thereby attenuating cGAS-STING activation and interferon expression. These findings shed light on the metabolic adaptations and immune escape driven by androgen receptor signaling inhibitors, potentially informing the development of more effective and durable therapeutic approaches in the near future.
Insights
Prostate cancer resistance to enzalutamide involves metabolic changes that suppress the immune system. Upregulated ketogenic pathways lead to beta-hydroxybutyrate accumulation, causing immune desertification and immunotherapy resistance.
Area of Science:
- Oncology
- Metabolic pathways
- Immunology
Background:
- Androgen receptor inhibitors are standard for metastatic prostate cancer.
- Rapid resistance development limits treatment efficacy.
- Enzalutamide resistance is associated with an immunosuppressive tumor microenvironment.
Purpose of the Study:
- Investigate the mechanisms linking enzalutamide resistance to immune escape.
- Identify metabolic adaptations driving resistance and immunosuppression.
- Explore potential therapeutic targets for overcoming resistance.
Main Methods:
- Analysis of enzalutamide-induced castration-resistant prostate cancer models.
- Assessment of ketogenic pathway enzyme expression.
- Investigation of beta-hydroxybutyrate (BHB) effects on protein modification (OTUD7B).
- Evaluation of cGAS-STING pathway activation and interferon expression.
Main Results:
- Marked overexpression of ketogenic pathway enzymes in resistant prostate cancer.
- Accumulation of BHB due to ketogenic pathway upregulation.
- BHB-mediated beta-hydroxybutyrylation of OTUD7B impaired APC/C substrate degradation.
- Reduced cytoplasmic dsDNA, attenuated cGAS-STING activation, and decreased interferon expression.
Conclusions:
- Metabolic reprogramming via the ketogenic pathway contributes to immune desertification in enzalutamide-resistant prostate cancer.
- BHB-driven OTUD7B modification is a key mechanism for immune evasion.
- Targeting metabolic adaptations may enhance immunotherapy efficacy in prostate cancer.
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