️ Episode 94: Intraindividual Epigenetic Heterogeneity in Advanced Prostate Cancer

In this episode of PaperCast Base by Base, we explore how integrated DNA methylation, RNA sequencing, and histone modification profiling across metastatic lesions reveal intraindividual epigenetic diversity underlying phenotypic subtypes of castration-resistant prostate cancer.

Study Highlights: The research team performed multi-omic profiling combining reduced representation bisulfite sequencing, RNA sequencing, and H3K27ac and H3K27me3 profiling across 98 metastatic lesions from patients with castration-resistant prostate cancer. They found that, although epigenetic and transcriptomic landscapes are generally stable within individual patients, certain metastases display outlier DNA methylation and expression patterns corresponding to divergent molecular subtypes. By integrating DNA methylation and histone mark data, the authors identified over 20,000 region-gene links implicating epigenetic regulation of key lineage genes, including ASCL1 and AR, as well as therapeutic targets such as PSMA and DLL3. Functional assays in AR-negative cell lines demonstrated that BMP4 signaling, modulated by epigenetic alterations, supports viability in double-negative prostate cancer.

Conclusion: This multi-omic study underscores the importance of intraindividual epigenetic heterogeneity in shaping therapeutic vulnerabilities and highlights the potential of cfDNA methylation profiling to guide precision treatment strategies.

Reference: Mizuno K, Ku S-Y, Venkadakrishnan VB, Bakht MK, Sigouros M, Chan J, Trigos A, Driskill JH, Manohar J, King A, Presser AG, Kim MJ, Tewari AK, Long HW, et al. Intraindividual epigenetic heterogeneity underlying phenotypic subtypes of advanced prostate cancer. Nat Commun. 2025;16:5543. doi:10.1038/s41467-025-60654-z

License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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