CHD1 Loss Reprograms SREBP2-Driven Cholesterol Synthesis To Fuel Androgen-Responsive Growth and Castration Resistance in Spop-Mutated Prostate Tumors

Authors

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

Publication Date

5-1-2025

Journal

Nature Cancer

DOI

10.1038/s43018-025-00952-z

PMID

40360905

PMCID

PMC12276840

PubMedCentral® Posted Date

7-20-2025

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Male, Humans, Prostatic Neoplasms, Castration-Resistant, Cholesterol, Sterol Regulatory Element Binding Protein 2, Repressor Proteins, Nuclear Proteins, Receptors, Androgen, DNA-Binding Proteins, Animals, Mutation, Mice, Cell Line, Tumor, DNA Helicases, Androgen Antagonists, Androgens, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic

Published Open-Access

yes

Recommended Citation

Chen, Feiyu; Li, Haoyan; Wang, Yin; et al., "CHD1 Loss Reprograms SREBP2-Driven Cholesterol Synthesis To Fuel Androgen-Responsive Growth and Castration Resistance in Spop-Mutated Prostate Tumors" (2025). Faculty, Staff and Student Publications. 4383.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4383