title: 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.
authors.affiliation: Stress and Cancer Laboratory, Equipe Labelisée LNCC, Institut Curie, Paris Cedex 05, France Inserm, U830, Paris, France.
authors.forename: Tina
authors.initials: T
authors.lastname: Gruosso
authors.affiliation: Stress and Cancer Laboratory, Equipe Labelisée LNCC, Institut Curie, Paris Cedex 05, France Inserm, U830, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Mieulet
authors.affiliation: Stress and Cancer Laboratory, Equipe Labelisée LNCC, Institut Curie, Paris Cedex 05, France Inserm, U830, Paris, France.
authors.forename: Melissa
authors.initials: M
authors.lastname: Cardon
authors.affiliation: Stress and Cancer Laboratory, Equipe Labelisée LNCC, Institut Curie, Paris Cedex 05, France Inserm, U830, Paris, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bourachot
authors.affiliation: Stress and Cancer Laboratory, Equipe Labelisée LNCC, Institut Curie, Paris Cedex 05, France Inserm, U830, Paris, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Kieffer
authors.affiliation: Institut Curie, CNRS UMR3347, INSERM U1021, University Paris-Sud 11, Orsay, France.
authors.forename: Flavien
authors.initials: F
authors.lastname: Devun
authors.affiliation: Department of Translational Research, Institut Curie, Paris Cedex 05, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Dubois
authors.affiliation: Institut Curie, CNRS UMR3347, INSERM U1021, University Paris-Sud 11, Orsay, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Dutreix
authors.affiliation: Department of Tumour Biology, Institut Curie, Paris Cedex 05, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA.
authors.forename: Kyle Malcolm
authors.initials: KM
authors.lastname: Miller
authors.affiliation: Stress and Cancer Laboratory, Equipe Labelisée LNCC, Institut Curie, Paris Cedex 05, France Inserm, U830, Paris, France fatima.mechta-grigoriou@curie.fr.
authors.forename: Fatima
authors.identifier: 0000-0002-3751-6989
authors.initials: F
authors.lastname: Mechta-Grigoriou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006657:Histones / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D051267:NF-E2-Related Factor 2; D046988:Proteasome Endopeptidase Complex; D044767:Ubiquitin-Protein Ligases; C495636:Nfe2l2 protein, mouse; C579124:RNF168 protein, mouse; C475961:gamma-H2AX protein, mouse
keywords: JUND; NRF2; RNF168; Triple‐Negative breast cancer; ubiquitination