As tumors grow, poor vascularization and increasing metabolic activity drive tumors into hypoxia, a condition that paradoxically promotes pluripotency as well as the emergence of stem-like cells in the evolving tumor hypoxic niches ( 11). Removal of these marks is canonically mediated by iron/2-oxoglutarateвЂ“dependent members of the JmJC domainвЂ“containing histone demethylase family (KDM) that require oxygen as an indispensable cofactor ( 9, 10). In particular, the reactivation of Oct-4, SOX2, and Nanog, a triad of stemness transcription factors involved in tumor progression toward metastasis ( 5), requires demethylation of repressive epigenetic marks associated with heterochromatin maintenance, including H3K9me3 and H3K27me3 ( 6вЂ“ 8). Overwhelming evidence indicates that the reactivation of pluripotency genes normally silenced in adult somatic cells promotes lineage plasticity acquisition in tumor cells ( 3, 4), enabling metastatic dissemination. Therefore, our results indicate that FeSOD2 is a demethylase with unique activities and functions in the promotion of cancer evolution toward metastatic phenotypes.Д¬ancer cell evolution toward developing metastatic potential depends in large part on the loss of lineage commitment simultaneous to the acquisition of phenotypic plasticity ( 1, 2). FeSOD2 operating as H3 demethylase requires H 2O 2 as substrate, which unlike cofactors of canonical demethylases (i.e., oxygen and 2-oxoglutarate), is more abundant in tumor cells than in normal tissue. Phenotypically, cells expressing nucleus-targeted SOD2 (NLS-SOD2) have increased clonogenicity and metastatic potential. Particularly, H3K9me3 was specifically removed from regulatory regions upstream of Nanog and Oct-4, two pluripotency factors involved in cancer stem cell reprogramming. Acetylated, iron-bound SOD2 localizes to the nucleus, promoting stem cell gene expression via removal of suppressive epigenetic marks such as H3K9me3 and H3K927me3. 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. However, a distinctive activity underlying its tumor-promoting function is yet to be described. 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.

Immunoprecipitation western blot