Nuclear-localized, iron-bound superoxide dismutase-2 antagonizes epithelial lineage programs to promote stemness of breast cancer cells via a histone demethylase activity.
Diego R CoelhoFlavio R PalmaVeronica PavianiChenxia HeJeanne M DanesYunping HuangJuliana C P CaladoPeter C HartCristina M FurduiLeslie B PooleMatthew John SchipmaMarcelo G BoniniPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- amyotrophic lateral sclerosis
- cancer stem cells
- gene expression
- stem cells
- dna methylation
- papillary thyroid
- squamous cell carcinoma
- small cell lung cancer
- breast cancer cells
- squamous cell
- induced apoptosis
- hydrogen peroxide
- iron deficiency
- public health
- epithelial mesenchymal transition
- signaling pathway
- nitric oxide
- cell cycle arrest
- climate change
- childhood cancer
- endoplasmic reticulum stress
- bone marrow