Cisplatin-Induced Oxidative Stress Regulates YAP to Modulate Epigenome Promoting the Survival of Osteosarcoma Cells

The widely used chemotherapeutic drug cisplatin (CDDP) is an integral part of the preoperative chemotherapy protocol for high-grade osteosarcoma (OS). However, despite an aggressive treatment regimen, drug refractoriness is a major hindrance to successful therapy. We previously identified key transcriptomic alterations that support the survival of OS cells following CDDP exposure. In the present study, our in vitro analyses further demonstrate that CDDP treatment promotes an adaptive, ROS-dependent enrichment of the repressive histone mark H3K27me3 at the upstream promoter regions of growth-associated genes such as CCNA2, as well as at the promoter of LATS1, a negative regulator of Yes-Associated Protein (YAP). This enrichment contributes to the transcriptional repression of these genes and is associated with growth arrest; notably, quenching of reactive oxygen species with N-acetyl cysteine (NAC) reversed this effect. Furthermore, reduced LATS1 expression was associated with increased nuclear localization of YAP. Importantly, pharmacological inhibition or genetic ablation of YAP attenuated the CDDP-induced accumulation of repressive marks. Mechanistically, YAP was found to colocalize and coimmunoprecipitate with EZH2, the catalytic member of the Polycomb Repressive Complex 2 (PRC2), suggesting a potential role for YAP in facilitating EZH2-mediated transcriptional repression. Consistent with these observations, inhibition of YAP or pharmacological reversal of the repressive chromatin state using a histone deacetylase (HDAC) inhibitor enhanced the sensitivity of the OS cells to low-dose CDDP treatment. Overall, the present study demonstrates an interplay among oxidative stress, epigenetics, and YAP in modulating OS cell fate post-CDDP exposure.