SOD2 acetylation on lysine 68 promotes stem cell reprogramming in breast cancer

Significance Mitochondrial superoxide dismutase (SOD2) has been established as a suppressor of tumor initiation. However, late-stage solid tumors display high levels of SOD2 expression. Here, we report that overexpression of SOD2 causes its accumulation in an acetylated form that increases mitochondrial reactive oxygen species as well as HIF2α activity. HIF2α is a potent promoter of cancer stem cell formation, which is largely responsible for treatment failure and metastatic recurrence of breast cancer. In agreement, we found increased SOD2 and HIF2α in metastatic lesions compared with primary tumors from the same patients. Taken together, our results indicate that the accumulation of acetylated SOD2 observed in late-stage cancer may drive cancer stem cell formation, contributing to tumor aggressiveness and poorer outcomes.