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.
Abstract
The dichotomous behavior of superoxide dismutase-2 (SOD2) in cancer biology has long been acknowledged and more recently linked to different posttranslational forms of the enzyme. However, a distinctive activity underlying its tumor-promoting function is yet to be described. Here, we report that acetylation, one of such posttranslational modifications (PTMs), increases SOD2 affinity for iron, effectively changing the biochemical function of this enzyme from that of an antioxidant to a demethylase. Acetylated, iron-bound SOD2 localizes to the nucleus, promoting stem cell gene expression via removal of suppressive epigenetic marks such as H3K9me3 and H3K927me3. Particularly, H3K9me3 was specifically removed from regulatory regions upstream of Nanog and Oct-4, two pluripotency factors involved in cancer stem cell reprogramming. Phenotypically, cells expressing nucleus-targeted SOD2 (NLS-SOD2) have increased clonogenicity and metastatic potential. FeSOD2 operating as H3 demethylase requires H2O2 as substrate, which unlike cofactors of canonical demethylases (i.e., oxygen and 2-oxoglutarate), is more abundant in tumor cells than in normal tissue. Therefore, our results indicate that FeSOD2 is a demethylase with unique activities and functions in the promotion of cancer evolution toward metastatic phenotypes.
