2. Academic Validation
  3. The mitochondrial translocation of phosphorylated EZH2 promotes PARP inhibitor resistance in BRCA1-deficient epithelial ovarian cancer

The mitochondrial translocation of phosphorylated EZH2 promotes PARP inhibitor resistance in BRCA1-deficient epithelial ovarian cancer

  • Cell Discov. 2026 Mar 12;12(1):17. doi: 10.1038/s41421-026-00880-x.
Ling Hu # 1 2,  Xiaolu Ma # 1 2,  Xushan Cai # 3,  Tianqing Yan # 1 2,  Kaixia Zhou 1 2,  Chen Shan 1 2,  Ning Guo 1 2,  Hui Zheng 1 2,  Yanchun Wang 1 2,  Ying Tong 1 2,  Suhong Xie 1 2,  Heng Zhang 1 2,  Cuncun Chen 1 2,  Zhiyun Gong 1 2,  Lin Guo 1 2,  Renquan Lu 4 5
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, China.
  • 2 Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, China.
  • 3 School of Life Science and Technology, Tongji University, Shanghai, China.
  • 4 Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, China. [email protected].
  • 5 Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41820330 DOI: 10.1038/s41421-026-00880-x
Abstract

BRCA1-deficient epithelial ovarian Cancer (EOC) is reported to respond to poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis); however, acquired resistance frequently emerges, limiting the long-term clinical efficacy of PARPis. The mechanisms driving acquired PARPi resistance in these patients remain poorly understood. In this study, we performed a systemic screen of epigenetic inhibitors in patient-derived organoids (PDOs) and identified enhancer of zeste homolog 2 (EZH2) as the key driver of PARPi resistance in BRCA1-deficient EOC. We found that in PARPi-resistant cells, intracellular EZH2 translocated from the nucleus to the mitochondria, where it promoted mitochondrial fusion and subsequently prevented PARPi-mediated Apoptosis. Mechanistically, we determined that PARPi treatment activated YES1 to phosphorylate EZH2 at the Y728 residue, which promoted the mitochondrial translocation of EZH2 in a TOM20-dependent manner. Using mass spectrometry, we identified MYO19 as a main substrate of EZH2 in mitochondria and found that EZH2 trimethylated MYO19 at the K928 residue to trigger mitochondrial fusion. Moreover, Y728 phosphorylation also increased EZH2 protein stability by hindering TRIM4 binding, thus blocking TRIM4-mediated ubiquitination and subsequent proteasomal degradation. Notably, the efficacy of targeting YES1 or EZH2 to resensitize tumors to PARPis was validated in PDOs, xenograft models and EOC cell lines. Here, our findings reveal a YES1-EZH2-MYO19 post-translational modification cascade, whereby PARPi-induced phosphorylation of EZH2 triggered mitochondrial fusion, and targeting phosphorylated EZH2 rebalanced mitochondrial dynamics and resensitized BRCA1-deficient EOC to PARPis, suggesting a promising therapeutic strategy.

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