Targeting the DNA methylation-H3K27me3 switch reverses castration resistance and immunosuppression via ADAMTS1-driven collagenolysis

• 成果类型: Article
• 署名作者: Wu, Xiang; Song, Xiaoyi; Li, Bo; Yang, Yuchun; Li, Kunyu; Zhu, Jun; Li, Yawei; Yang, Xinming; Dai, Yingbo; Zhang, Zhuangzhuang
• 署名单位: Sun Yat Sen University; Sun Yat Sen University; Sun Yat Sen University; Anhui Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2525431123
• 发表日期: 2026-06-23
• 页码: e2525431123
• 关键词: CRPC; epigenetic switch; extracellular matrix remodeling; ADAMTS1; dual epigenetic therapy; CANCER STATISTICS; prostate-cancer; chromatin; mechanisms; genes

摘要

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.