The mitochondrial translocation of phosphorylated EZH2 promotes PARP inhibitor resistance in BRCA1-deficient epithelial ovarian cancer - PubMed
7 hours ago
- #PARP inhibitor resistance
- #mitochondrial dynamics
- #BRCA1-deficient ovarian cancer
- BRCA1-deficient epithelial ovarian cancer (EOC) often develops resistance to PARP inhibitors (PARPis), limiting their long-term efficacy.
- A systemic screen identified EZH2 as a key driver of PARPi resistance in BRCA1-deficient EOC.
- In PARPi-resistant cells, EZH2 translocates from the nucleus to mitochondria, promoting mitochondrial fusion and preventing apoptosis.
- PARPi treatment activates YES1, which phosphorylates EZH2 at Y728, facilitating its mitochondrial translocation via TOM20.
- EZH2 trimethylates MYO19 at K928 in mitochondria, triggering mitochondrial fusion.
- Y728 phosphorylation stabilizes EZH2 by blocking TRIM4-mediated ubiquitination and degradation.
- Targeting YES1 or EZH2 resensitizes BRCA1-deficient EOC to PARPis in patient-derived organoids, xenograft models, and cell lines.
- The study suggests a therapeutic strategy targeting the YES1-EZH2-MYO19 cascade to overcome PARPi resistance.