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Integrative analysis identifies the atypical repressor E2F8 as a targetable transcriptional activator driving lethal prostate cancer

Oncogene volume 44, pages 481–493 (2025)Cite this article

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Abstract

Acquired resistance to androgen receptor (AR)-targeted therapies underscores the need to identify alternative therapeutic targets for treating lethal prostate cancer. In this study, we evaluated the prognostic significance of 1635 human transcription factors (TFs) by analyzing castration-resistant prostate cancer (CRPC) datasets from the West and East Stand Up to Cancer (SU2C) cohorts. Through this screening approach, we identified E2F8, a putative transcriptional repressor, as a TF consistently associated with poorer patient outcomes in both cohorts. Notably, E2F8 is highly expressed and active in AR-negative CRPC compared to AR-positive CRPC. Integrative profiling of E2F8 cistromes and transcriptomes in AR-negative CRPC cells revealed that E2F8 directly and non-canonically activates target oncogenes involved in cancer-associated pathways. To target E2F8 in CRPC, we employed the CRISPR/CasRx system to knockdown E2F8 mRNA, resulting in effective and specific downregulation of E2F8 and its target oncogenes, as well as significant growth inhibition in AR-negative CRPC in both cultured cells and xenograft models. Our findings identify and characterize E2F8 as a targetable transcriptional activator driving CRPC, particularly the growth of AR-negative CRPC.

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Fig. 1: Identification of E2F8 as a putative oncogenic TF through in silico screening of PCa datasets.
Fig. 2: E2F8 is an oncogenic TF in AR-negative PCa.
Fig. 3: Characterization of E2F8-regulated cistromes and transcriptomes in AR-negative PC3 and DU145 cells.
Fig. 4: Functional characterization of E2F8-activated target genes.
Fig. 5: CRISPR/CasRx-mediated potent knockdown of E2F8 mRNA with high specificity.
Fig. 6: Nanoparticle-based CRISPR/CasRx/pre-gE2F8 treatment inhibits prostate tumor growth in xenograft mouse models.
Fig. 7: TT3 LLN effectively delivers CasRx/pre-gE2F8 RNA into engrafted DU145 tumors with no toxicity.

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Data availability

ChIP-seq and RNA-seq data have been deposited at the NCBI Gene Expression Omnibus (GEO) with accession number of GSE275631.

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Acknowledgements

We thank Duke BioRepository & Precision Pathology Center for tissue sections and HE staining. We also thank Ling Wang from the Animal Histopathology and Laboratory Medicine Core at UNC-Chapel Hill for performing animal hematological and clinical chemistry tests.

Funding

This work was supported by the Department of Defense (DoD) Early Investigator Award (W81XWH-22-1-0039 to FH) and by the Department of Pathology, Duke University School of Medicine (to QW).

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Authors and Affiliations

  1. Department of Pathology, Duke University School of Medicine, Durham, NC, USA

    Furong Huang, Kexin Li, Zhong Chen, Zhifen Cui, William Hankey, Hongyan Wang & Qianben Wang

  2. Data Science Institute, MCW Cancer Center and Mellowes Center for Genome Science and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    Kun Fang & Victor X. Jin

  3. Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Biomedical Engineering and Imaging Institute, Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jingyue Yan & Yizhou Dong

  4. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA

    Qianben Wang

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Contributions

QW, FH, and WH conceptualized and designed the study; WH performed the initial screening of TFs correlation analysis with patient survival. FH and KL performed ChIP-seq and RNA-seq experiments; ZC, KF, VXJ, and FH analyzed the results from ChIP-seq and RNA-seq experiment; YD provided TT3 LLN and experimental guidance for in vivo nanotherapy study; JY synthesized the CasRx mRNA; Z.Cui performed encapsulation of CasRx mRNA and pre-gE2F8 oligos, or luciferase mRNA with TT3 LLN; FH and KL performed therapeutic assessment of TT3 encapsulating CasRx/pre-gE2F8 system in mice; WH and HW provided constructive discussion and contributed to manuscript writing and editing; FH, KL, and QW wrote the manuscript, with all authors contributing to the writing and providing feedback.

Corresponding author

Correspondence to Qianben Wang.

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Competing interests

QW, ZC, and YD are inventors on a patent filed by Duke University that relates to the research reported in this paper. The remaining authors declare no competing interests.

Ethics approval and consent to participate

All methods were performed in accordance with the relevant guidelines and regulations. All animal experiments were conducted in accordance with the guidelines of the Association for Assessment and Accreditation of Laboratory Animal Care International and the protocol (A176-21-08-24) approved by Duke University Medical Center Institutional Animal Care and Use Committee. Clinical and expression data of prostate cancer patients were obtained from publicly available repositories and were anonymized before access. Informed consent from patients was obtained through the respective dataset sources. This study does not involve identifiable images from human research participants.

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Huang, F., Li, K., Chen, Z. et al. Integrative analysis identifies the atypical repressor E2F8 as a targetable transcriptional activator driving lethal prostate cancer. Oncogene 44, 481–493 (2025). https://doi.org/10.1038/s41388-024-03239-2

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