Chen Feiyu, Li Haoyan, Wang Yin, Tang Ximing, Lin Kevin, Li Qidong, Meng Chenling, Shi Wei, Leo Javier, Liang Xin, Zhang Jie, Van Vivien, Mahmud Iqbal, Wei Bo, Lorenzi Philip L, Raso Maria G, Aparicio Ana, Lu Yue, Frigo Daniel E, Gan Boyi, Zhao Di
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nat Cancer. 2025 May 13. doi: 10.1038/s43018-025-00952-z.
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.
尽管接受了去势治疗，但大多数前列腺癌（PCa）患者仍会进展为去势抵抗性前列腺癌（CRPC），其中雄激素受体（AR）仍然是一个重要的驱动因素。SPOP和CHD1的同时发生的基因改变定义了一种独特的PCa亚型，但它们在肿瘤进展和治疗反应中的相互作用仍不清楚。在这里，我们提供了基因证据，支持CHD1缺失会加速携带SPOP突变的PCa男性患者的疾病进展并赋予其去势抵抗性。通过利用基因工程和多组学技术，我们发现了CHD1在通过抑制SREBP2转录组进行脂质代谢重编程中的非规范功能。CHD1的缺失会诱导胆固醇生成，为肿瘤内雄激素生物合成提供原料并增强AR活性，从而导致携带SPOP突变的PCa产生去势抵抗性。将抗雄激素治疗与降胆固醇药物联合使用，对携带CHD1缺失和SPOP突变的CRPC显示出协同且持久的活性。这些发现增进了我们对一种新兴PCa亚型的理解，并为CRPC男性患者提供了生物标志物驱动的联合治疗策略。
