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<p>Platinum resistance in breast cancer remains a major therapeutic challenge due to convergent escape mechanisms. Here, we identify the PRMT6/USP7 complex as a dual epigenetic orchestrator of chemoresistance. Mechanistically, USP7-mediated deubiquitination of H2BK120ub facilitates PRMT6-dependent deposition of the repressive mark H3R2me2a, concomitant with the exclusion of activating H3K4me3. This coordinated histone crosstalk reprograms the chromatin landscape, leading to transcriptional silencing of the ferroptosis regulator TAZ (WWTR1). Consequently, TAZ suppression disrupts lipid peroxidation and blocks cisplatin-induced ferroptosis, a critical cell death pathway. Simultaneously, the PRMT6/USP7 complex recruits the E3 ubiquitin ligase RNF168 to sites of DNA damage, promoting H2AX monoubiquitination and robust activation of both homologous recombination (HR) and non-homologous end-joining (NHEJ) repair pathways, thereby enhancing DNA damage tolerance. To translate this mechanism, we engineered an injectable hydrogel for the sequential co-delivery of cisplatin and PRMT6/USP7 inhibitors, demonstrating significantly enhanced therapeutic efficacy. Our study unveils a previously unrecognized bifunctional role for the PRMT6-USP7 axis in orchestrating epigenetic reprogramming and DNA repair to confer platinum resistance, providing profound mechanistic insights and a compelling co-targeting strategy for overcoming chemoresistance in breast cancer.</p><p></p>

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Targeting the USP7-PRMT6 epigenetic axis overcomes chemoresistance in breast cancer by coordinating H3R2me2a deposition and RNF168 methylation for DNA repair and ferroptosis blockade

  • 期刊论文

  • 发表日期：

    2026年1月31日

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  • Tianshu Yang,
  • Hong Wen,
  • Jing Zhang,
  • Yiyang Pan,
  • Feng Yang,
  • Xuan Wu,
  • Jun Zhao,
  • Ke Peng,
  • Lijie Yang,
  • Jie Mei,
  • Yujiao Cai,
  • Yan Wang,
  • Weidong Xiao

摘要

Platinum resistance in breast cancer remains a major therapeutic challenge due to convergent escape mechanisms. Here, we identify the PRMT6/USP7 complex as a dual epigenetic orchestrator of chemoresistance. Mechanistically, USP7-mediated deubiquitination of H2BK120ub facilitates PRMT6-dependent deposition of the repressive mark H3R2me2a, concomitant with the exclusion of activating H3K4me3. This coordinated histone crosstalk reprograms the chromatin landscape, leading to transcriptional silencing of the ferroptosis regulator TAZ (WWTR1). Consequently, TAZ suppression disrupts lipid peroxidation and blocks cisplatin-induced ferroptosis, a critical cell death pathway. Simultaneously, the PRMT6/USP7 complex recruits the E3 ubiquitin ligase RNF168 to sites of DNA damage, promoting H2AX monoubiquitination and robust activation of both homologous recombination (HR) and non-homologous end-joining (NHEJ) repair pathways, thereby enhancing DNA damage tolerance. To translate this mechanism, we engineered an injectable hydrogel for the sequential co-delivery of cisplatin and PRMT6/USP7 inhibitors, demonstrating significantly enhanced therapeutic efficacy. Our study unveils a previously unrecognized bifunctional role for the PRMT6-USP7 axis in orchestrating epigenetic reprogramming and DNA repair to confer platinum resistance, providing profound mechanistic insights and a compelling co-targeting strategy for overcoming chemoresistance in breast cancer.