CHD1 Loss Reprograms SREBP2-Driven Cholesterol Synthesis to Fuel Androgen-Responsive Growth and Castration Resistance in SPOP-Mutated Prostate Tumors - Beyond the Abstract
In our recent study, we investigated a specific and increasingly recognized subtype of PCa defined by concurrent SPOP mutations and CHD1 loss. While SPOP is the most frequently mutated gene in localized PCa, and CHD1 is often co-deleted in these tumors, their biological interplay in therapy responses has remained unclear. By integrating state-of-the-art genetic engineering models and cutting-edge technologies, we reveal a compelling mechanistic link between CHD1 loss and castration resistance in SPOP-mutated PCa.
Our findings establish CHD1 as a suppressor of the cholesterol biosynthesis pathway. In SPOP-mutant tumors, loss of CHD1 unleashes the cholesterol synthesis machinery and provides critical substrate for intratumoral androgen production, thereby retaining AR signaling and supporting tumor growth under castration conditions. In essence, CHD1 loss rewires cellular metabolism in a way that confers therapeutic resistance and drives disease progression.
For the first time, we link CHD1 to cancer metabolism and uncover its crucial role in reprogramming cholesterol biosynthesis. By upregulating transcriptional factor SREBF2, CHD1 loss induces the rate-limiting enzymes catalyzing cholesterol biosynthesis, facilitating cholesterol production. In men, androgens are synthesized from cholesterol and are produced primarily in the testicles and adrenal glands. In PCa patients who undergo surgical or chemical castration, testicle-derived androgen is shut down, whereas de novo androgen synthesis in adrenal glands and prostate tumors is compensatorily increased and becomes one of the driving mechanisms leading to CRPC progression. The increased cholesterol in CHD1-deficient prostate tumors provides precursors for intratumoral androgen synthesis, which confers castration resistance in PCa patients.
As a tumor suppressor in PCa, SPOP plays a vital role in controlling the degradation of AR and co-activators and modulating androgen homeostasis. Prostate tumors with SPOP mutations are driven by and dependent on AR signaling. By contrast, CHD1 exerts oncogenic or tumor-suppressive functions by interacting with different genetic alterations. Here, we demonstrate that CHD1 loss promotes SPOP-mutated tumor progression and facilitates castration resistance, broadening our understanding of CHD1 biology in this genetic subtype. Even though CHD1 deletion-driven intratumoral cholesterol and androgen biosynthesis are independent of SPOP or AR, SPOP mutation-induced AR protein stabilization and AR dependency in prostate tumors provide a vital premise for CHD1 deletion promoting PCa progression and castration resistance. Our discovery of the mutually beneficial relationship between CHD1 loss and SPOP mutations not only helps us understand the biological significance of their co-occurrence in cancer genomes but also provides insights into personalized therapeutic strategies for SPOP-mutated PCa with or without CHD1 deletion.
SPOP mutation has become an emerging predictive biomarker for ADT in clinics. It is associated with improved survival outcomes after castration or AR axis-targeted therapy. Despite the CHD1 gene being deleted in half of SPOP-mutated PCa, its status was not assessed in these large-scale clinical studies due to the limitations of genetic determination assays. Our findings in preclinical models suggested that CHD1 deletion renders SPOP-mutated PCa more resistant to castration and facilitates the development of CRPC, underscoring the importance of utilizing CHD1 genetic status as a potent biomarker in future clinical trial design and applications of anti-androgen therapies.
Most importantly, we designed an effective combinatorial therapy for CRPC containing CHD1 deletion and SPOP mutations, i.e., combining commonly used, safe cholesterol-lowering drugs (statins) with anti-androgen therapy (abiraterone). Statins are FDA-approved drugs, and their utilization has been associated with reduced risks, better outcomes, and longer ADT duration in PCa patients. Most recently, a large Phase III clinical trial is ongoing to determine the impact of atorvastatin on castration resistance and PCa progression during ADT (NCT04026230). Our studies suggest that genetic defects of CHD1 and SPOP might be potential molecular biomarkers for predicting the response to atorvastatin and informing patient selection in this clinical trial. The combinatorial strategy we developed in this study also has a high translational potential and might lead to new perspective biomarker-driven clinical trials for men with CRPC.
Of note, genetic alterations of CHD1 are also frequently observed in estrogen-dependent cancers. Although this study mainly focuses on androgen biosynthesis and PCa biology, the regulatory effects of CHD1 on cholesterol production are AR-independent. Given that cholesterol also serves as a precursor for estrogen biosynthesis, CHD1-deficient cholesterol production might also contribute to the progression of estrogen-dependent cancers and influence their response to hormone therapy. If that is the case, the strategies of targeting cholesterol biosynthesis alone or combined with anti-estrogen therapy might also be effective in estrogen-dependent cancers containing CHD1 defects.
In conclusion, our studies provide new insights into a unique PCa subtype with CHD1 deletion and SPOP mutations, advance our knowledge of CHD1 biology and its role during cancer progression, and inform biomarker-driven combinatorial therapy for men with lethal CRPC.
Written by: Feiyu Chen and Di Zhao, Experimental Radiation Oncology, UT MD Anderson Cancer Center, Houston, TX, USA
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Cholesterol Synthesis Fuels Androgen Growth in SPOP/CHD1-Altered Prostate Tumors - Di Zhao