Open AccessChronic oxidative stress promotes H2 AX protein degradation and enhances chemosensitivity in breast cancer patients
Author(s) -
Gruosso Tina,
Mieulet Virginie,
Cardon Melissa,
Bourachot Brigitte,
Kieffer Yann,
Devun Flavien,
Dubois Thierry,
Dutreix Marie,
VincentSalomon Anne,
Miller Kyle Malcolm,
MechtaGrigoriou Fatima
Publication year - 2016
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201505891
Subject(s) - oxidative stress , cancer , breast cancer , cancer research , degradation (telecommunications) , medicine , chemistry , computer science , telecommunications
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 H2 AX , a key player in DNA repair. We observe that persistent accumulation of ROS , due to a deficient JunD‐/Nrf2‐antioxidant response, reduces H2 AX protein levels. This effect is mediated by an enhanced interaction of H2 AX with the E3 ubiquitin ligase RNF 168, which is associated with H2 AX poly‐ubiquitination and promotes its degradation by the proteasome. ROS ‐mediated H2 AX decrease plays a crucial role in chemosensitivity. Indeed, cycles of chemotherapy that sustainably increase ROS reduce H2 AX protein levels in Triple‐Negative breast cancer ( TNBC ) patients. H2 AX decrease by such treatment is associated with an impaired NRF 2‐antioxidant response and is indicative of the therapeutic efficiency and survival of TNBC patients. Thus, our data describe a novel ROS ‐mediated regulation of H2 AX turnover, which provides new insights into genetic instability and treatment efficacy in TNBC patients.