Talazoparib enhances the anti-angiogenic potential of quinacrine through the deregulation of P300 and GCN5 chromatin remodelers in patient-derived oral cancer stem cells.

Angiogenesis plays a crucial role in cancer progression. However, the role of PARP1 in regulating chromatin remodelers and activating pro-angiogenic factors in cancer stem cells (CSCs) remains poorly understood. This study systematically investigates the detailed molecular mechanism through which PARP1 and its associated chromatin remodelers, P300 and GCN5, regulate angiogenesis in ex vivo patient-derived oral mucosa cancer stem cells (PD-OMCSCs). To investigate this mechanism, we used a combination of experimental approaches, including CAM assays, tube formation assays, biochemical analyses (western blot, gelatin zymography, and ELISA), molecular imaging (tissue immunofluorescence), and protein-protein interaction (co-immunoprecipitation and in silico study). Comparative analyses revealed significantly higher expression of PARP1, P300, and GCN5 in oral cancer tissues compared to normal ones. Co-immunoprecipitation and docking studies confirmed their mutual interactions, forming a chromatin-remodeling complex (PARP1-P300-GCN5) that facilitates angiogenic gene activation and expression. Quinacrine (QC), in combination with PARP inhibitor Talazoparib, disrupted this complex, leading to significant downregulation of VEGFA expression, reduced MMP activity, and suppression of angiogenic markers (Ang-1, Ang-2, TGF-β, CXCL-12, VEGFC, HIF-1α, and IL-6). These effects collectively impaired endothelial cell tube formation and blood vessel development in both HUVECs and CAM models. Furthermore, individual knockdown of PARP1, P300, or GCN5 reduced VEGFA expression, indicating their important role in regulating tumor angiogenesis. In conclusion, the QC and Talazoparib combination effectively prevents the activation and secretion of angiogenic factors, thereby suppressing angiogenesis, and may serve as a promising therapeutic approach for oral cancer by targeting PARP1 and associated chromatin remodelers.