In a recent study published in Genes & Diseases, researchers from Gongli Hospital of Shanghai Pudong New Area, Shanghai University of Traditional Chinese Medicine, Tongji University School of Medicine, and Shanghai Jiao Tong University School of Medicine utilized unbiased integrative bioinformatics analysis and molecular experimental validation to identify three prostate cancer-specific targets and their respective high-affinity small-molecule inhibitors.

Through genome-wide screening, the authors identified a seven-gene core signature—comprising SNRPF, RFC3, WDR75, RAD51, CDC20, DTL, and RRM2—associated with poor disease-free survival; consequently, CRISPR-Cas9 or siRNA-mediated knockdown of CDRs (CDC20 (cell division cycle 20), DTL (denticleless E3 ubiquitin protein ligase), and RRM2 (ribonucleotide reductase M2)) suppressed tumor growth. The authors also observed a significant correlation between each of the CDRs and patient survival across multiple cohorts, which, together with their increased expression during prostate cancer progression, highlights the oncogenic potential of these genes.

The increased expression of these CDRs during disease progression, particularly in neuroendocrine prostate cancer (NEPC), a lethal stage of prostate cancer characterized by diminished AR signaling pathway and poor response to androgen deprivation therapies, underscores their oncogenic potential in lethal, AR-independent stages of the disease.
Integrative co-expression and GSEA across various prostate cancer cohorts revealed substantial overlap in gene sets associated with these CDRs, enriched for G2/M checkpoint and cell division pathways. Functional validation using CRISPR-Cas13 knockdown demonstrated that silencing these genes inhibits tumor growth in both AR-dependent and AR-independent cells by inducing G2/M cell cycle arrest via increased p-CDK1 levels.

Mechanistically, this study established that the RB1/ E2F1 axis regulates CDRs. Using ChIP-sequencing and qPCR, the authors confirmed that E2F1 directly binds to CDR promoters, while the loss of RB1 significantly upregulates their expression.

To identify potential therapeutic agents, the authors performed a structure-based virtual screening of over 1,200 diverse molecules against the CDR proteins, identifying three potent inhibitors—Q199, XDD60, and A79—which demonstrated significant growth suppression across both AR-active and AR-inactive cell lines, compared with enzalutamide, a clinically prevalent AR antagonist. Furthermore, combining low doses of Q199, XDD60, and A79 exerted a powerful synergistic effect, markedly inhibiting tumor growth.

This study has certain limitations: i) focusing only on transcriptomic data and non-inclusion of proteomic and phosphoproteomic datasets, and ii) the lack of in vivo validation to establish the safety and toxicity of the lead compounds.

In summary, this study revealed the RB1/E2F1/CDR axis as a key driver of advanced prostate cancer progression and NEPC characteristics; by integrating functional genomics with virtual screening, the authors identified potent lead compounds that synergistically inhibit tumor growth in AR-independent models. Collectively, these findings establish a high-throughput paradigm for the development of targeted therapies to manage lethal prostate cancer.

Reference

Title of the original paper: Integrative high-throughput studies to develop novel targets and drug for the treatment of advanced prostate cancer

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101732

Funding Information:

• National Natural Science Foundation of China (No. 82473185, 82202922)
• Key Discipline Development Initiative of the Shanghai Health System (China) (No. 2024ZDXK0043)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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