SOD2 acetylation on lysine 68 promotes stem cell reprogramming in breast cancer
Menée in vitro et à l'aide d'un modèle murin de cancer mammaire, cette étude met en évidence un mécanisme par lequel l'acétylation de la lysine 68 de la superoxyde dismutase mitochondriale SOD2 favorise le développement de cellules souches cancéreuses via la voie de signalisation du facteur induit par l'hypoxie HIF2alpha
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.Mitochondrial superoxide dismutase (SOD2) suppresses tumor initiation but promotes invasion and dissemination of tumor cells at later stages of the disease. The mechanism of this functional switch remains poorly defined. Our results indicate that as SOD2 expression increases acetylation of lysine 68 ensues. Acetylated SOD2 promotes hypoxic signaling via increased mitochondrial reactive oxygen species (mtROS). mtROS, in turn, stabilize hypoxia-induced factor 2α (HIF2α), a transcription factor upstream of “stemness” genes such as Oct4, Sox2, and Nanog. In this sense, our findings indicate that SOD2K68Ac and mtROS are linked to stemness reprogramming in breast cancer cells via HIF2α signaling. Based on these findings we propose that, as tumors evolve, the accumulation of SOD2K68Ac turns on a mitochondrial pathway to stemness that depends on HIF2α and may be relevant for the progression of breast cancer toward poor outcomes.