LAUSR

Significance The main finding reported here is that acetylation converts superoxide dismutase-2 (SOD2) from a mitochondrial antioxidant to a nuclear histone demethylase. The change in function involves the binding of iron instead of the canonical cofactor manganese. Unlike well-characterized histone demethylases, FeSOD2 uses H2O2, which is typically increased in hypoxic tumor niches, as substrate. Along these lines, we found that nuclear FeSOD2 promotes lineage plasticity largely by facilitating the reactivation of gene expression associated with epithelial-to-mesenchymal transition and stemness reprogramming. Together, our results provide evidence in support of an acetylation-dependent nucleus-specific function of SOD2 associated with the emergence of more tumorigenic and metastatic cancer cell phenotypes.