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

Author:

Coelho Diego R.12ORCID,Palma Flavio R.12ORCID,Paviani Veronica12,He Chenxia3,Danes Jeanne M.12,Huang Yunping12ORCID,Calado Juliana C. P.12,Hart Peter C.4ORCID,Furdui Cristina M.5ORCID,Poole Leslie B.6ORCID,Schipma Matthew J.27ORCID,Bonini Marcelo G.12

Affiliation:

1. Department of Medicine, Division of Hematology Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

2. Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

3. Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI 53226

4. College of Science, Health and Pharmacy, Roosevelt University, Schaumburg, IL 60173

5. Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157

6. Department of Biochemistry, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157

7. Quantitative Data Sciences Core and Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

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.

Funder

HHS | NIH | National Cancer Institute

HHS | NIH | National Institute of Environmental Health Sciences

HHS | NIH | National Institute of Allergy and Infectious Diseases

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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