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

Nature Cancer volume 6, pages 854–873 (2025)Cite this article

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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.

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Fig. 1: Combined CHD1 deletion and SPOP mutation promote prostate tumorigenesis.
Fig. 2: CHD1 deletion confers resistance to castration in SPOP-mutant PCa.
Fig. 3: CHD1 deletion retains AR signaling in SPOP-mutant PCa following castration.
Fig. 4: CHD1 deletion promotes cholesterol biosynthesis and intratumoral androgen production.
Fig. 5: CHD1–SNF2H complex governs the expression of cholesterol biosynthesis genes by repressing SREBF2 expression.
Fig. 6: SREBP2 is required for intratumoral cholesterol and androgen synthesis driven by CHD1 deletion.
Fig. 7: Abiraterone synergizes with atorvastatin in suppressing CHD1-deleted/SPOP-mutant PCa cells.
Fig. 8: Abiraterone combined with cholesterol-lowering drugs shows therapeutic potential in CHD1-deleted/SPOP-mutant CRPC.

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Data availability

CUT&RUN-seq data supporting this study’s findings have been deposited in the Gene Expression Omnibus (GEO) under accession code GSE272802. scRNA-seq data generated in this study have been deposited in the GEO under accession code GSE273102. Metabolism profiling data are available in Supplementary Table 2. The CHD1 RIME dataset generated in this study has been deposited in the PRIDE (ProteomeXchange) database under accession code PXD061854. Previously published scRNA-seq data that were reanalyzed here are available under accession code GSE210358 (ref. 50). The human pan-cancer and PCa genomic and bulk RNA-seq data46 were derived from the TCGA Research Network (http://cancergenome.nih.gov/). The human metastatic PCa genomic and bulk RNA-seq data were derived from the SU2C/PCF metastatic PCa dataset53, which is available at www.cbiportal.org and has been deposited in GitHub at https://github.com/cBioPortal/datahub/tree/master/public/prad_su2c_2019. Source data are provided with this paper. All other data supporting the findings of this study are available from the corresponding author upon reasonable request

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Acknowledgements

We thank R. A. DePinho at The University of Texas MD Anderson for sharing the P and PC mouse models. We thank A. Sutton, who is in Editing Services of the Research Medical Library at MD Anderson, for editing the article. We also acknowledge the MD Anderson Small Animal Imaging Facility (supported by NIH/NCI P30 CA016672 Cancer Center Support Grant), Metabolomics Core Facility (supported by NIH/NCI P30 CA016672 Cancer Center Support Grant) and CCSG Research Histology Core Laboratory (supported by NIH/NCI P30 CA016672 Cancer Center Support Grant). D.E.F. has been supported by NIH R01 CA275138, DOD/PCRP W81XWH-22-1-0686 and DOD/PCRP W81XWH-22-1-0187. B.G. has been supported by RP230072 from the Cancer Prevention & Research Institute of Texas (CPRIT) and R01CA181196, R01CA244144, R01CA247992 and R01CA269646 from the NIH. D.Z. is a CPRIT Scholar in Cancer Research and has been supported by the CPRIT Recruitment of First-Time Tenure-Track Faculty Award RR190021, NIH R00 CA226360, NIH R01 CA275990 and CA278889, Prostate Cancer Foundation Challenge Award FP00016492 and DOD CDMRP IDA award PC230358. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Author notes

  1. These authors contributed equally: Feiyu Chen, Haoyan Li.

Authors and Affiliations

  1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Feiyu Chen, Haoyan Li, Yin Wang, Qidong Li, Chenling Meng, Wei Shi, Javier Leo, Xin Liang, Jie Zhang, Boyi Gan & Di Zhao

  2. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ximing Tang & Maria G. Raso

  3. Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Kevin Lin & Yue Lu

  4. UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Javier Leo

  5. Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Vivien Van

  6. Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Iqbal Mahmud, Bo Wei & Philip L. Lorenzi

  7. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ana Aparicio & Daniel E. Frigo

  8. Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Daniel E. Frigo

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Contributions

F.C., H.L. and D.Z. designed the research. F.C. and D.Z. wrote the main text of the manuscript, and H.L. wrote part of the Methods. F.C. performed experiments other than those listed below. H.L. prepared samples for lipidomic profiling and RIME and did initial data analysis, prepared CUT&RUN samples for sequencing and performed co-IP, ChIP–qPCR, luciferase assays and some experiments related to SREBP2 and SNF2H. D.Z. conducted the clinical relevance analysis and scRNA-seq analysis. Y.W. provided mouse husbandry of GEMM mice and assisted in surgical castration and histopathologic staining. X.T. and M.G.R. performed pathological analyses. K.L. and Y.L. performed CUT&RUN-seq data analysis and supported RIME data analysis. Q.L. performed part of the western blotting. C.M. provided SPOP-mutant plasmids and provided technical support. W.S., J.L. and X.L. provided technical support. J.Z. assisted in preparing pathological samples. V.V. aided in conducting MRI scanning. I.M., B.W. and P.L.L. performed lipidomic profiling and data analysis. A.A., D.E.F. and B.G. provided intellectual contributions throughout the project.

Corresponding author

Correspondence to Di Zhao.

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Competing interests

D.E.F. has received research funding from GTx and has a familial relationship with March Biosciences, Biocity Biopharmaceuticals, Hummingbird Bioscience and Barricade Therapeutics. The other authors declare no competing interests.

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Nature Cancer thanks Scott Cramer, David Labbé, Jean-Philippe Theurillat and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Combined CHD1Del and SPOPMut Promote Prostate Tumorigenesis.

a, Co-occurrence of CHD1Del and SPOPMut in prostate adenocarcinoma (Log2 Odds Ratio > 3; p < 0.001). Oncoprint was generated from cbioportal. b, Quantification of MRI of prostate tumors from 10-month-old male PC (n = 8 mice), PSp (n = 8 mice), and PCSp (n = 19 mice). c, Histopathology analysis of prostate tumors from PC, PSp, and PCSp male GEMM mice. AP: anterior prostate lobes; VP: ventral prostate lobes; DLP: dorsal and lateral prostate lobes. d, Histopathology analysis revealed the total area of carcinoma region in prostate tumors from male PC (n = 8 mice), PSp (n = 8 mice), and PCSp (n = 6 mice). e, IHC staining (Ser473-phosphorylated AKT; CHD1; Flag; AR and Ki67) of prostate tumors from PC, PSp, and PCSp male GEMM mice at 6 months of age. Representative images are from AP lobes. Scale bar = 50 μm. Data (b) are presented as the mean ± standard deviation. Experiments were performed at least three times with similar results. One-way ANOVA with Tukey’s post hoc tests (b) was performed using GraphPad Prism v.9.2.0.

Source data

Extended Data Fig. 2 CHD1Del confers resistance to castration in SPOPMut PCa.

a-b, Histologic analysis of Ki67 and Cleaved caspase-3 in PCSp prostate tumors with or without surgical castration (n = 3 tumors per group). Tumors that showed response or resistance to castration were compared. Representative images are from anterior prostate (AP) lobes. Cx: Castration. Scale bar = 50 μm. c, Western blot assays of MyC-Cap cells expressing SPOPMut (W131G) with or without Chd1 knockout (KO). Sp, SPOPW131G; CSp, SPOPW131G/Chd1KO. d, Growth curves of Sp and CSp MyC-CaP cells overexpressing vector control (CSp-Vec) or CHD1 (CSp-CHD1) cultured in medium supplied with regular FBS (Normal) or charcoal-stripped FBS (CS). n = 3 biological replicates. e, MYC IHC staining in Sp and CSp MyC-Cap tumors with or without castration. Scale bar = 50 μm. f, Quantification of Ki67 IHC staining in Sp and CSp MyC-Cap tumors with or without castration (n = 3 tumors per group). g, Western blot assays of LNCaP cells expressing SPOP mutation (W131G) with or without Chd1 knockout (KO). Sp, SPOPW131G; CSp, SPOPW131G/CHD1KO. h, Quantification of Ki67 IHC staining in Sp and CSp LNCaP xenograft tumors with or without castration (n = 3 tumors per group). i, Western blot assays of LAPC4 cells expressing SPOP mutants with or without CHD1 depletion. j, Growth curves of SPOPMut LAPC4 cells with or without CHD1 depletion cultured in medium supplied with regular FBS (Normal) or charcoal-stripped FBS (CS) (n = 3 biological replicates per group). Data in b, d, f, h and j are presented as the mean ± standard deviation. Experiments were performed at least three times with similar results. Two-tailed unpaired Student’s t-test (d and j) or one-way ANOVA with Tukey’s post hoc tests (b, f, and h) was performed using GraphPad Prism v.9.2.0.

Source data

Extended Data Fig. 3 CHD1Del retains AR signaling in SPOPMut PCa upon castration.

a, Representative images of GFP+ organoids derived from P and PC GEMMs, cultured with different dosages of DHT for 6 days. Each GFP+ dot indicates an organoids. Scale bar = 2000 μm. b-c, Histopathology analysis of P and PC tumor organoids cultured with or without DHT (n = 3 organoid samples per group). Scale bar = 50 μm. d, Representative images and quantification of AR IHC staining in prostate tumors from PSp and PCSp GEM mice with or without castration (n = 3 tumors). Representative images are from anterior prostate (AP) lobes. Cx: Castration. Scale bar = 50 μm. e, Expression of AR and target genes in P and PC tumor organoids in the absence of DHT, as determined by qPCR (n = 3 biological replicates). f, qPCR analysis of TMPTRSS2 expression in Sp (SPOPW131G) and CSp (SPOPW131G/CHD1KO) MyC-CaP cells cultured in the CS medium (n = 3 biological replicates). g, Western blot assays of LNCaP cells expressing SPOP mutants with or without CHD1 depletion. h, mRNA expression of AR and target genes in LNCaP cells with or without CHD1 knockout, cultured in the CS medium (n = 3 biological replicates). i, V5-tagged CHD1 was overexpressed in CHD1-depleted LNCaP cells, followed by the determination of AR target genes using qPCR (n = 3 biological replicates). j, ChIP-qPCR in control and CHD1 knockout LNCaP cells revealed that CHD1 loss increased AR binding to enhancer regions of PSA and TMPRSS2 genes (n = 3 biological replicates). k, CHD1 expression in 29,861 single epithelial cells from n = 13 mCRPC patients (scRNA-seq dataset, GSE210358). Data (c-f and h-j) presented as the mean ± standard deviation. Experiments were performed at least three times with similar results. Unpaired two-tailed Student’s t-test (e, f, h and j), one-way ANOVA with Tukey’s post hoc test (d and i), or two-way ANOVA (c) with Tukey’s post hoc test were performed using GraphPad Prism v.9.2.0.

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Extended Data Fig. 4 Single-cell transcriptomic profiling of PSp and PCSp GEMMs.

a-e, ScRNA-seq was performed in prostate tumors from PSp and PCSp GEMM mice one month after surgical castration (n = 2 mice per group). a, The UMAP views of 22,943 single cells color-coded by nine major clusters (C1-C9). b, The bubble plot presents marker gene expression for each cluster, where dot size and color represent the percentage of marker gene expression and the averaged scaled expression value, respectively. c, The UMAP view of prostate epithelial cells color-coded by two genotype groups. d, The violin plot of CHD1 gene expression for each subcluster in PSp versus PCSp samples. e, UMAP views of prostate epithelial cells, color-coded by the count of signature genes in indicated pathways. Two-tailed Wilcoxon tests (d) were performed using Bioturing.

Extended Data Fig. 5 CHD1Del promotes cholesterol biosynthesis and intratumoral androgen production.

a, Heatmap displaying the abundance of all 1013 lipid metabolites in control versus CHD1-depleted LNCaP cells cultured in CS medium. b, Principal Component Analysis (PCA) scores plot for spectral data of lipid metabolites from control and CHD1-depleted LNCaP cells. c, The abundance of each category of lipid metabolites in control versus CHD1-depleted LNCaP cells cultured in CS medium (n = 3 biological replicates). The full name of each lipid metabolite is listed in Supplemental Table 2. d, g, Control and CHD1-depleted LNCaP cells expressing wildtype SPOP or W131G mutant were cultured in CS medium, followed by the determination of cholesterol (d, n = 3 biological replicates) and testosterone (g, n = 6 biological replicates). e, h, MyC-CaP cells expressing SPOPW131G with or without CHD1 depletion were cultured in CS medium. Cells and culture media were collected to determine total cholesterol (e, n = 3 biological replicates) and testosterone (h, n = 3 biological replicates), respectively. f, Total cholesterol and cholesterol esters in P, PC, PSp, and PCSp organoids cultured in the DHT-free medium (n = 3 biological replicates). i, Enrichment of cholesterol metabolism geneset in SPOPMut prostate tumors with or without CHD1Del, determined by Gene Set Enrichment Analysis (GSEA). The normalized Enrichment Score (NES) and False Discovery Rate (FDR) q-value are shown. Data are presented as the mean ± standard deviation. Experiments were performed at least three times with similar results. Two-tailed unpaired Student’s t-test (c, e, g, and h) or one-way ANOVA (d and f) with Tukey’s post hoc tests were performed using GraphPad Prism v.9.2.0.

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Extended Data Fig. 6 CHD1Del promotes cholesterol biosynthesis enzymes by inducing SREBP2 expression.

a-d, qPCR and Western blot analysis of indicated genes in LNCaP cells expressing SPOPMut (W131G or F102C) with or without CHD1 knockout (clone A or C) cultured in normal or charcoal-stripped (CS) medium (n = 3 biological replicates for qPCR assays). e-f, mRNA levels of indicated genes in LAPC4 or Myc-Cap cells expressing SPOPW131G with or without CHD1 depletion (n = 3 biological replicates for qPCR assays). g, mRNA expression of indicated genes in Sp (SPOPW131G) and CSp (SPOPW131G/CHD1KO) LNCaP cells cultured in the normal medium, CS medium, or CS medium supplied with cholesterol (Ch, 30 μM) (n = 3 biological replicates). h, Western blot analysis of SREBP2 in CHD1-depleted LNCap cells upon CHD1 re-expression. i, Expression of CHD1 and SREBF2 in tumors with different CHD1 copy number variation (CNV) (Pan-Cancer TCGA dataset). j, Pearson correlation analysis of CHD1 expression with SREBF2 and its target genes in metastatic PCa containing SPOPMut (n = 13 patients; SU2C/PCF dataset). Data are presented as the mean ± standard deviation. Experiments were performed at least three times with similar results. Two-tailed unpaired Student’s t-test (a, c, e, and f) or one-way ANOVA with Tukey’s post hoc tests (g and i) were performed using GraphPad Prism v.9.2.0.

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Extended Data Fig. 7 Non-canonical function of CHD1 in repressing SREBP2 by interacting with SNF2H/ACF1 complex.

a, ChIP-Seq profile showing the binding of CHD1 to the promoter region of the Srebf2 gene in murine PCa cells. Two antibodies against CHD1 were used for ChIP-seq. b, Peptide coverage of the bait protein (CHD1) and its interacting protein SNF2H, as determined by RIME. Regions shown in blue represent peptides detected by mass spectrometry for each protein. c, Co-IP assays were performed in C4-2 and PC3-M cells using CHD1 antibody, followed by Western blot analysis of CHD1 and SNF2H. d, Western blot analysis of SNF2H in control and CHD1-depleted LNCaP cells. e, ChIP was performed using IgG, CHD1, and SNF2H antibodies in LNCaP cells cultured in CS medium. The binding of CHD1 and SNF2H proteins to the promoter region of the SREBF2 gene was determined using qPCR (n = 3 biological replicates). The locations of primers (P1-P6) in the up- or down-stream of SREBF2’s transcription start site (TSS) and Exon 1 (E1) region are shown. f, Expression of HMGCS1 in control and CHD1-depleted LNCaP cells with or without SNF2H (SMARCA5) knockdown (n = 3 biological replicates). g, CUT&RUN tracks illustrating the binding of SNF2H to the promoter region of the SREBF2 gene in SPOPMut LNCaP cells with or without CHD1 knockout. Data are presented as the mean ± standard deviation. Experiments were performed at least three times with similar results. Two-tailed unpaired Student’s t-test (e) or one-way ANOVA with Tukey’s post hoc tests (f) were performed using GraphPad Prism v.9.2.0.

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Extended Data Fig. 8 SREBP2 is required for intratumoral cholesterol and androgen synthesis driven by CHD1Del.

a-b, SPOPMut LNCaP cells with SREBF2 overexpression were cultured in CS medium for 48 hours, followed by the determination of SREBF2 gene expression (a) and production of total cholesterol and testosterone (b). c, Growth curves of SPOP-mutated LNCaP cells with SREBF2 overexpression cultured in CS medium for 6 days. Data represent the results of triplicates. d-e, Control and CHD1-depleted SPOPMut LNCaP cells were cultured in the CS medium, followed by treatment with Fatostatin (10 μM) for 24 hours. mRNA expression of SREBF2 target genes (d) and AR target genes (e) was determined by qPCR. f, Control and CHD1-depleted SPOPMut LNCaP cells were cultured in CS medium with or without Fatostatin (10 μM) for 6 days. Cell proliferation was determined, and growth curves were presented. g, PSp and PCSp organoids were cultured in the DHT-free medium, followed by treatment of Fatostatin (10 μM) for 6 days. FKBP5 gene expression was determined by qPCR. n = 3 biological replicates in all figures. Data in all figures are presented as the mean ± standard deviation. Experiments were performed at least three times with similar results. Two-tailed unpaired Student’s t-test (a, b, c, and f) or one-way ANOVA with Tukey’s post hoc tests (d, e and g) was performed using GraphPad Prism v.9.2.0.

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Extended Data Fig. 9 Abiraterone synergizes with atorvastatin in suppressing CHD1Del/SPOPMut PCa cells.

a, CHD1-depleted SPOP-mutated LNCaP cells were cultured in the charcoal-stripped (CS) medium, followed by treatment with Abiraterone at different doses for 48 hours. mRNA expression of SREBF2 and its target genes was determined by qPCR (n = 3 biological replicates). b-d, Dose-response matrix and drug interaction landscapes revealing the combination effects of Abiraterone (Abi) and Atorvastatin (Ato) on LNCaP (a,b), MyC-CaP (c), and LAPC4 (d) with or without SPOPW131G and CHD1 deletion. Drug interaction landscapes and synergy scores were generated using Synergyfinder. e, Representative GFP images of P organoids after 6-day treatment of Abiraterone or Atorvastatin, alone or in combination, in the absence of DHT. Scale bar = 2000 μm. f, H&E and IHC staining of indicated markers in P organoids treated with Abiraterone and/or Atorvastatin. Scale bar = 50 μm. g. Quantification of Ki67 (upper), Cleaved caspase-3 (middle), and AR (bottom) IHC staining in P organoids treated with Abiraterone or Atorvastatin, alone or in combination (n = 3 organoid samples per group). Data are presented as the mean ± standard deviation. Experiments were performed at least three times with similar results. One-way ANOVA with Dunnett’s post hoc tests (a) or one-way ANOVA with Tukey’s post hoc tests (g) were performed using GraphPad Prism v.9.2.0.

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Extended Data Fig. 10 Abiraterone combined with cholesterol-lowing drugs shows therapeutic potential in CHD1Del/SPOPMut CRPC.

a, Body weights of male PSp (n = 3 mice) and PCSp (n = 4 mice) were documented throughout the treatment period. b-c, MRI imaging and tumor volume quantification of prostate tumors from male PSp (n = 3 mice) before and after treatment with Abiraterone and Atorvastatin. Prostate tumor regions are circled with orange dashed lines. Cx: Castration. d, H&E and AR staining of prostate tumors from castrated PSp male mice, with and without combination treatment. Scale bar = 100 μm. Experiments were performed at least three times with similar results. Two-tailed paired Student’s t-test (c) was performed using GraphPad Prism v.9.2.0.

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Supplementary information

Supplementary Information

Supplementary Fig. 1. Gating strategy.

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Supplementary Tables 1–5

Supplementary Tables 1–5.

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Chen, F., Li, H., Wang, Y. et al. CHD1 loss reprograms SREBP2-driven cholesterol synthesis to fuel androgen-responsive growth and castration resistance in SPOP-mutated prostate tumors. Nat Cancer 6, 854–873 (2025). https://doi.org/10.1038/s43018-025-00952-z

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