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

EMBO Mol Med. 2016 May 2;8(5):527-49. doi: 10.15252/emmm.201505891. Print 2016 May.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Disease Models, Animal
  • Female
  • Histones / metabolism*
  • Mice
  • Mice, Knockout
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / pathology
  • Ubiquitin-Protein Ligases / metabolism


  • Antineoplastic Agents
  • H2AX protein, mouse
  • Histones
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • RNF168 protein, mouse
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex