Tumor cell metabolism is altered during leukemogenesis. Cells performing oxidative phosphorylation (OXPHOS) generate reactive oxygen species (ROS) through mitochondrial activity. To limit the deleterious effects of excess ROS, certain gene promoters contain antioxidant response elements (ARE), e.g. the genes NQO-1 and HO-1. ROS induces conformational changes in KEAP1 and releases NRF2, which activates AREs. We show in vitro and in vivo that OXPHOS induces, both in primary leukemic cells and cell lines, de novo expression of NQO-1 and HO-1 and also the MAPK ERK5 and decreases KEAP1 mRNA. ERK5 activates the transcription factor MEF2, which binds to the promoter of the miR-23a-27a-24-2 cluster. Newly generated miR-23a destabilizes KEAP1 mRNA by binding to its 3'UTR. Lower KEAP1 levels increase the basal expression of the NRF2-dependent genes NQO-1 and HO-1. Hence, leukemic cells performing OXPHOS, independently of de novo ROS production, generate an antioxidant response to protect themselves from ROS.
Bibliographical noteFunding Information:
All our funders are public or charitable organizations. This work was supported by the program “Chercheur d'avenir” from the Region Languedoc-Roussillon ( 09-13195 ) (MV), a scientific program from the “Communauté de Travail des Pyrénées” ( CTPP5/12 to MV), the charities CIEL, L'Un pour l'Autre and Ensangble ( 09/2013 ) (MV), a grant from the European Community Program SUDOE ( CLiNK SOE2/P1/E341 to MV), an AOI from the CHU Montpellier ( No. 221826 ) (GC and MV), a grant from Fondation de France ( 0057921 ) and fellowships from the Higher Education Commission, Pakistan (MGR and AK) and Ministère de l'Enseignement Supérieur et de la Recherche (MESR) (DNV). FACs analysis was performed at the platform Montpellier Rio Imaging (MRI). The collection of clinical data and samples (HEMODIAG_2020) at the CHRU Montpellier was supported by funding from Région Languedoc Roussillon . We thank Dr. Robert A. Hipskind for English correction of this manuscript.
- Antioxidant response elements (ARE)
- Oxidative phosphorylation (OXPHOS)