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. Coelho; Flavio R. Palma; Veronica Paviani; Chenxia He; Jeanne M. Danes; Yunping Huang; Juliana C.P. Calado; Peter C. Hart; Cristina M. Furdui; Leslie B. Poole; Matthew J. Schipma; Marcelo G. Bonini

doi:10.1073/pnas.2110348119

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. Coelho, Flavio R. Palma, Veronica Paviani, Chenxia He, Jeanne M. Danes, Yunping Huang, Juliana C.P. Calado, Peter C. Hart, Cristina M. Furdui, Leslie B. Poole, Matthew J. Schipma, Marcelo G. Bonini^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English (US)
Article number	e2110348119
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	29
DOIs	https://doi.org/10.1073/pnas.2110348119
State	Published - Jul 19 2022

Funding

ACKNOWLEDGMENTS. We acknowledge the technical assistance of David Kirchebeuchler from Center of Advanced Microscopy. Recombinant SOD2-K68Q was expressed and purified by Dr. Hyun Lee and Dr. Robel D. Demissie (Biophysics Core, University of Illinois Chicago). Elemental analysis was performed at the Northwestern University Quantitative Bio-Element Imaging Center generously supported by NASA Ames Research Center Grant NNA04CC36G. We are grateful for funding from the NIH, National Institute of Allergy and Infectious Diseases (NIAID) R01AI131267 (to M.G.B.); National Institute of Environmental Health Sciences (NIEHS) R01028149 (to M.G.B.); National Cancer Institute (NCI) R01CA216882 (to M.G.B.); the Liz and Eric Lefkofsky Foundation Innovation Award (to M.G.B.); and the Department of Defense/Army Research Office (DOD/ ARO) Grant 72983 (to M.G.B.).

Keywords

SOD2
breast cancer
epigenetic
iron
manganese

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.2110348119

Cite this

Coelho, D. R., Palma, F. R., Paviani, V., He, C., Danes, J. M., Huang, Y., Calado, J. C. P., Hart, P. C., Furdui, C. M., Poole, L. B., Schipma, M. J., & Bonini, M. G. (2022). Nuclear-localized, iron-bound superoxide dismutase-2 antagonizes epithelial lineage programs to promote stemness of breast cancer cells via a histone demethylase activity. Proceedings of the National Academy of Sciences of the United States of America, 119(29), Article e2110348119. https://doi.org/10.1073/pnas.2110348119

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title = "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 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.",

keywords = "SOD2, breast cancer, epigenetic, iron, manganese",

author = "Coelho, {Diego R.} and Palma, {Flavio R.} and Veronica Paviani and Chenxia He and Danes, {Jeanne M.} and Yunping Huang and Calado, {Juliana C.P.} and Hart, {Peter C.} and Furdui, {Cristina M.} and Poole, {Leslie B.} and Schipma, {Matthew J.} and Bonini, {Marcelo G.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 the Author(s).",

year = "2022",

month = jul,

day = "19",

doi = "10.1073/pnas.2110348119",

language = "English (US)",

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Coelho, DR, Palma, FR, Paviani, V, He, C, Danes, JM, Huang, Y, Calado, JCP, Hart, PC, Furdui, CM, Poole, LB, Schipma, MJ & Bonini, MG 2022, 'Nuclear-localized, iron-bound superoxide dismutase-2 antagonizes epithelial lineage programs to promote stemness of breast cancer cells via a histone demethylase activity', Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 29, e2110348119. https://doi.org/10.1073/pnas.2110348119

Nuclear-localized, iron-bound superoxide dismutase-2 antagonizes epithelial lineage programs to promote stemness of breast cancer cells via a histone demethylase activity. / Coelho, Diego R.; Palma, Flavio R.; Paviani, Veronica et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 119, No. 29, e2110348119, 19.07.2022.

Research output: Contribution to journal › Article › peer-review

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T1 - Nuclear-localized, iron-bound superoxide dismutase-2 antagonizes epithelial lineage programs to promote stemness of breast cancer cells via a histone demethylase activity

AU - Coelho, Diego R.

AU - Palma, Flavio R.

AU - Paviani, Veronica

AU - He, Chenxia

AU - Danes, Jeanne M.

AU - Huang, Yunping

AU - Calado, Juliana C.P.

AU - Hart, Peter C.

AU - Furdui, Cristina M.

AU - Poole, Leslie B.

AU - Schipma, Matthew J.

AU - Bonini, Marcelo G.

PY - 2022/7/19

Y1 - 2022/7/19

N2 - 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.

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KW - SOD2

KW - breast cancer

KW - epigenetic

KW - iron

KW - manganese

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Coelho DR, Palma FR, Paviani V, He C, Danes JM, Huang Y et al. Nuclear-localized, iron-bound superoxide dismutase-2 antagonizes epithelial lineage programs to promote stemness of breast cancer cells via a histone demethylase activity. Proceedings of the National Academy of Sciences of the United States of America. 2022 Jul 19;119(29):e2110348119. doi: 10.1073/pnas.2110348119

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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