Authors
Xiang Wu, Xiaoyi Song, Bo Li, Yuchun Yang, Kunyu Li, Jun Zhu, Yawei Li, Xinming Yang, Yingbo Dai, Zhuangzhuang Zhang
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 25. Pages e2525431123. Jun 23, 2026. Epub Jun 18, 2026.
Abstract
Castration-resistant prostate cancer (CRPC) lethality arises from epigenetic-driven resistance to androgen deprivation therapy (ADT). Here, we uncover a compensatory epigenetic switch between DNA methylation and H3K27me3-mediated repression as a critical barrier to epigenetic therapy in CRPC. Integrative multiomics analyses reveal that DNMT inhibitors (DNMTis) trigger EZH2-dependent H3K27me3 accumulation at the ADAMTS1 locus-a master collagenase essential for extracellular matrix (ECM) remodeling-perpetuating fibrotic niche formation and therapy resistance. Dual targeting of DNMTs and EZH2 disrupts this epigenetic plasticity, synergistically reactivating ADAMTS1 to degrade collagen-rich stroma, suppress FAK/MAPK mechanotransduction signaling, and reverse epithelial-mesenchymal transition (EMT). Crucially, in immunocompetent models, this strategy achieves >90% tumor suppression and reverses immunosuppression by enhancing cytotoxic CD8+ T cell infiltration 11.4-fold while depleting immunosuppressive macrophages and Tregs. Mechanistically, dual therapy inactivates the FAK/MAPK/EMT axis via ADAMTS1-mediated ECM degradation, overcoming stromal-mediated resistance. Our work establishes epigenetic-ECM coevolution as a hallmark of CRPC and provides a rationally designed combination therapy to dismantle the therapy-resistant niche.
PMID:
42313934
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.
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