Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients.
EMBO Mol Med, 2016/05;8(5):527-49.
Gruosso T[1], Mieulet V[1], Cardon M[1], Bourachot B[1], Kieffer Y[1], Devun F[2], Dubois T[3], Dutreix M[2], Vincent-Salomon A[4], Miller KM[5], Mechta-Grigoriou F[6]
Affiliations
PMID: 27006338DOI: 10.15252/emmm.201505891
Impact factor: 14.26
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.
Keywords: JUND; NRF2; RNF168; Triple‐Negative breast cancer; ubiquitination
MeSH terms
Animals; Antineoplastic Agents; Disease Models, Animal; Female; Histones; Mice; Mice, Knockout; NF-E2-Related Factor 2; Oxidative Stress; Proteasome Endopeptidase Complex; Proteolysis; Triple Negative Breast Neoplasms; Ubiquitin-Protein Ligases
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