Nuclear-localized, iron-bound superoxide dismutase-2 antagonizes epithelial lineage programs to promote stemness of breast cancer cells via a histone demethylase activity

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 H 2 O 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. Therefore, our results indicate that FeSOD2 is a demethylase with unique activities and functions in the promotion of cancer evolution toward metastatic phenotypes.

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“…8C & D ). Recent research indicates that SOD2 protein localization determines its functions within cells in relation to levels of specific transition metals such as iron (Fe) 94, 95 , therefore the iron-regulatory hepcidin (HAMP) expression within MG63 cells was evaluated. HAMP is a VDR-dependent antibacterial protein that inhibits ferroportin-mediated export of cellular iron into circulation 41 , and intriguingly, 1,25(OH) 2 D significantly downregulated HAMP mRNA in MG63 cells ( Fig.…”

“…SOD2 also functions non-canonically in the nucleus by decondensing chromatin to regulate gene expression, which in turn determines self-renewing capacity and lineage plasticity to increase metastatic potential 94 . Given the increased nuclear SOD2 in untreated MG63 cells, the non-canonical SOD2 signaling pathway was further investigated following 1,25(OH) 2 D treatment.…”

“…In support of this, our previous research had shown that 1,25(OH) 2 D mediates antioxidant functions in OS cells by specifically lowering mitochondrial O 2 − levels 90 . Elsewhere, breast cancer cells exhibit nuclear SOD2 as well as chromatin decondensation at genes involved in self renewal, dedifferentiation, and stemness reprogramming, resulting in increased metastatic potential 94 . Interestingly, new research has also revealed that SOD2 incorporated with iron (FeSOD2) functions as a nuclear pro-oxidant peroxidase, increasing oxidative stress 95 .…”