Abstract 6367: CHD1 loss hijacks SREBP2-mediated cholesterol biosynthesis to fuel SPOP-deficient prostate cancer and confers resistance to castration

Abstract Despite receiving surgical or medical castration, most prostate cancer (PCa) patients eventually progress to castration-resistant prostate cancer (CRPC), where the androgen receptor (AR) continues to drive disease progression. Genomic studies have identified a unique subtype of PCa marked by mutations in speckle-type BTB/POZ protein (SPOP), which lead to the stabilization of AR and its co-activators and have been associated with prolonged responses to androgen deprivation therapies and favorable prognoses. However, SPOP mutations frequently co-occur with the loss of chromodomain helicase DNA-binding protein 1 (CHD1), and the impact of concurrent CHD1 loss on SPOP-mutated PCa remains unclear. In this study, we developed a novel genetically engineered mouse model with CHD1 deletion and SPOP mutation to recapitulate this specific molecular subtype of PCa. Our findings provide genetic evidence that CHD1 loss accelerates the progression of SPOP-mutated PCa in males and confers resistance to castration in this context. By integrating single-cell transcriptomic, lipidomic, epigenetic, and proteomic analyses, we uncovered a non-canonical role of CHD1 in gene repression through its interaction with the ACF complex and demonstrated that CHD1 reprograms cholesterol metabolism by modulating sterol regulatory element-binding protein 2 (SREBP2). The loss of CHD1 triggers increased cholesterol production, supporting intratumoral androgen biosynthesis and sustaining AR transcriptional activity in SPOP-mutated prostate tumors, leading to castration resistance. Moreover, our studies reveal that combining the androgen synthesis inhibitor abiraterone with cholesterol-lowering agents exerts synergistic and durable anti-tumor effects against CRPC with CHD1 loss and SPOP mutations in males. These findings advance our understanding of an emerging PCa subtype and mechanism of action, as well as provide novel strategies for biomarker-driven combination therapy for patients with CRPC. Citation Format: Feiyu Chen, Haoyan Li, Yin Wang, Ximing Tang, Kevin Lin, Qidong Li, Chenling Meng, Wei Shi, Javier Leo, Xin Liang, Jie Zhang, Vivien Van, Iqbal Mahmud, Bo Wei, Philip L. Lorenzi, Maria G. Raso, Ana Aparicio, Yue Lu, Daniel E. Frigo, Boyi Gan, Di Zhao. CHD1 loss hijacks SREBP2-mediated cholesterol biosynthesis to fuel SPOP-deficient prostate cancer and confers resistance to castration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6367.