Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients

Abstract

Anti‐cancer drugs often increase reactive oxygen species (ROS) and cause DNA damage. Here, we highlight a new cross talk between chronic oxidative stress and the histone variant H2AX, a key player in DNA repair. We observe that persistent accumulation of ROS, due to a deficient JunD‐/Nrf2‐antioxidant response, reduces H2AX protein levels. This effect is mediated by an enhanced interaction of H2AX with the E3 ubiquitin ligase RNF168, which is associated with H2AX poly‐ubiquitination and promotes its degradation by the proteasome. ROS‐mediated H2AX decrease plays a crucial role in chemosensitivity. Indeed, cycles of chemotherapy that sustainably increase ROS reduce H2AX protein levels in Triple‐Negative breast cancer (TNBC) patients. H2AX decrease by such treatment is associated with an impaired NRF2‐antioxidant response and is indicative of the therapeutic efficiency and survival of TNBC patients. Thus, our data describe a novel ROS‐mediated regulation of H2AX turnover, which provides new insights into genetic instability and treatment efficacy in TNBC patients. This work gives new insights into the regulation of H2AX protein turnover under chronic oxidative stress that affects DNA damage response. H2AX degradation upon chronic stress sensitizes tumour cells to chemotherapy and is indicative of better survival in triple‐negative breast cancer patients. This work gives new insights into the regulation of H2AX protein turnover under chronic oxidative stress that affects DNA damage response. H2AX degradation upon chronic stress sensitizes tumour cells to chemotherapy and is indicative of better survival in triple‐negative breast cancer patients.