PRC2 governs HR proficiency and chemosensitivity in ovarian cancer via SQSTM1-mediated chromatin ubiquitination

Platinum and poly (ADP-ribose) polymerase (PARP) inhibitors are cornerstone therapies for ovarian cancer (OC), and their efficacy relies on homologous recombination deficiency (HRD), leaving more than 50% of HRD-negative OC patients with limited treatment options. This study investigated the epigenetic regulator, Polycomb Repressive Complex 2 (PRC2), as both a potential modulator of homologous recombination (HR) status and a candidate therapeutic target in ovarian cancer. We demonstrated that a triple combination regimen comprising PRC2 inhibitors, cisplatin, and PARP inhibitors induced synthetic lethality in BRCA-wild-type ovarian cancer. Functionally, PRC2 inhibition exacerbated cisplatin-induced DNA double-strand breaks. Further analysis showed that this resulted from compromised HR repair, as evidenced by impaired formation of BRCA1 and RAD51 repair foci. Mechanistically, chromatin-binding proteomics identified the autophagy receptor sequestosome-1 (SQSTM1) as a key downstream effector necessary for PRC2-mediated assembly of repair complexes, where it contributed to PRC2-regulated HR repair through reshaping chromatin ubiquitination. Critically, depletion of SQSTM1 attenuated the HR-promoting function of PRC2. For clinical translation, the synthetic lethality was further validated in patient-derived organoids (PDOs) and patient-derived xenografts (PDXs). Moreover, maintenance therapy combining PRC2 and PARP inhibitors following cisplatin chemotherapy has been identified as an optimal strategy. Collectively, our study revealed a novel PRC2-SQSTM1-HR regulatory axis, established PRC2 inhibition as a promising strategy to sensitize HRD-negative OCs to conventional therapies, and provided a strong mechanistic rationale for a new combination treatment paradigm.