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Updated: May 15, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
CHD1 loss reprograms SREBP2-driven cholesterol synthesis to fuel androgen-responsive growth and castration resistance
Feiyu Chen1, Haoyan Li1, Yin Wang1
1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
Despite undergoing castration, most individuals with prostate cancer (PCa) experience progression to castration-resistant PCa (CRPC), in which the androgen receptor (AR) remains an important driver. Concurrent genetic alterations in SPOP and CHD1 define a unique subtype of PCa, but their interactions in tumor progression and therapy response remain unclear. Here, we provide genetic evidence supporting that CHD1 loss accelerates disease progression and confers resistance to castration in males with SPOP-mutated PCa. By leveraging genetic engineering and multiomics, we uncovered a noncanonical function of CHD1 in lipid metabolism reprogramming via repressing the SREBP2 transcriptome. Loss of CHD1 induces cholesterol production, supplies intratumoral androgen biosynthesis and enhances AR activity, leading to castration resistance of SPOP-mutated PCa. Combining anti-androgen therapy with cholesterol-lowering drugs showed synergistic and durable activity against CRPC harboring CHD1 loss and SPOP mutations. These findings advance our understanding of an emerging PCa subtype and offer biomarker-driven combinatorial treatment strategies for men with CRPC.
Insights
Loss of CHD1 accelerates prostate cancer progression and castration resistance by altering lipid metabolism. Combining anti-androgen therapy with cholesterol-lowering drugs shows promise for treating this specific prostate cancer subtype.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Prostate cancer (PCa) often progresses to castration-resistant PCa (CRPC) despite treatment.
- The androgen receptor (AR) remains a key driver in CRPC.
- A unique PCa subtype with SPOP and CHD1 mutations presents therapeutic challenges.
Purpose of the Study:
- Investigate the role of CHD1 loss in SPOP-mutated PCa progression and castration resistance.
- Elucidate the molecular mechanisms linking CHD1 to tumor growth and therapy response.
- Identify novel therapeutic strategies for CRPC with SPOP/CHD1 alterations.
Main Methods:
- Genetic engineering in mouse models.
- Multiomics analysis (genomics, transcriptomics, metabolomics).
- In vitro and in vivo functional assays.
Main Results:
- CHD1 loss accelerates PCa progression and castration resistance in SPOP-mutated tumors.
- CHD1 regulates lipid metabolism by repressing SREBP2, leading to increased cholesterol production.
- Loss of CHD1 enhances intratumoral androgen biosynthesis and AR activity.
- Combined anti-androgen and cholesterol-lowering therapy demonstrated synergistic efficacy against CRPC with CHD1 loss and SPOP mutations.
Conclusions:
- CHD1 loss promotes CRPC through lipid metabolism reprogramming and enhanced AR signaling.
- Targeting cholesterol synthesis alongside androgen deprivation offers a promising therapeutic approach for this PCa subtype.
- These findings provide a foundation for biomarker-driven treatment strategies in CRPC.
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