文章：

CHD1缺失重编程srebp2驱动的胆固醇合成，在spop突变的前列腺肿瘤中促进雄激素响应性生长和去势抵抗

CHD1 loss reprograms SREBP2-driven cholesterol synthesis to fuel androgen-responsive growth and castration resistance in SPOP-mutated prostate tumors 

原文发布日期：2025-05-13 

英文摘要：

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. 

摘要翻译：

尽管接受阉割，大多数前列腺癌（PCa）患者会发展为去雄后进展的转移性前列腺癌（CRPC），其中和rogen受体（AR）仍是一个重要因素。SPOP和CHD1突变同时发生是PCa的一种独特亚型，但它们在肿瘤进展和治疗反应中的相互作用尚不明确。在此处，我们提供了一定的遗传证据表明，男性携带SPOP突变的PCa中，CHD1丢失会加速疾病进展并导致去雄耐受性。通过利用基因工程和多组学技术，我们揭示了CHD1在脂质代谢再编程中的非典型功能，通过抑制SREBP2转录来实现这一功能。CHD1丢失会促进胆固醇的产生，为肿瘤内和rogen的合成提供支持，并增强AR活性，从而使SPOP突变相关的人发生成忍性。联合使用反雄激素治疗和降脂药物对携带CHD1丢失和SPOP突变的转移性前列腺癌患者具有协同且持久的作用。这些发现有助于我们更好地理解这一新兴的PCa亚型，并为患有CRPC的男性提供基于生物标志物的组合治疗方法。

 原文链接：

https://www.nature.com/articles/s43018-025-00952-z