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

## TL;DR

This study finds that phosphorylated EZH2 moves to mitochondria in BRCA1-deficient ovarian cancer, causing resistance to PARP inhibitors, and targeting it could restore treatment effectiveness.

## Contribution

The study identifies a novel post-translational modification cascade involving YES1, EZH2, and MYO19 that drives PARP inhibitor resistance in BRCA1-deficient ovarian cancer.

## Key findings

- Phosphorylated EZH2 translocates to mitochondria and promotes mitochondrial fusion in PARP inhibitor-resistant cells.
- Targeting YES1 or EZH2 resensitizes BRCA1-deficient ovarian cancer to PARP inhibitors in preclinical models.
- EZH2 trimethylates MYO19 at K928, contributing to mitochondrial fusion and resistance.

## 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.