Acetylation activates an alternative function of SOD2 as a stemness factor in breast cancer

Mitochondrial superoxide dismutase (SOD2) displays a dichotomous role in cancer, being a suppressor of tumor initiation while stimulating cancer progression later in the established disease. The mechanistic basis of this switch remains unknown. Our results indicate that an increase in SOD2 expression beyond a defined threshold leads to its accumulation in an acetylated state and the activation of redox stress responses including, as reported here, the activation of hypoxic signaling. Specifically, we found that increased expression of SOD2/Ac-SOD2 stabilizes hypoxia-induced factor 2α (HIF2α) in a H 2 O 2 -dependent manner. Consequently, the SOD2/HIF2α promotes core stemness gene (i.e. Oct4 and SOX2) expression increasing the cancer stem cell (CSC) subpopulation, tumorigenicity and invasiveness of breast cancer cells. Based on these findings we propose that as tumors evolve to advanced stages a mitochondrial pathway dependent on SOD2/ROS and HIF2α is activated and contributes to CSC formation. It is also proposed that a SOD2 high /HIF2α + may identify cells in breast cancer with tumor initiating capacity and high metastatic potential.