SOD2 acetylation on lysine 68 promotes stem cell reprogramming in breast cancer

Chenxia He; Jeanne M. Danes; Peter C. Hart; Yueming Zhu; Yunping Huang; Andre Luelsdorf de Abreu; Joseph O’Brien; Angela J. Mathison; Binwu Tang; Jonna M. Frasor; Lalage M. Wakefield; Douglas Ganini; Erich Stauder; Jacek Zielonka; Benjamin N. Gantner; Raul A. Urrutia; David Gius; Marcelo G. Bonini

doi:10.1073/pnas.1902308116

SOD2 acetylation on lysine 68 promotes stem cell reprogramming in breast cancer

Chenxia He, Jeanne M. Danes, Peter C. Hart, Yueming Zhu, Yunping Huang, Andre Luelsdorf de Abreu, Joseph O’Brien, Angela J. Mathison, Binwu Tang, Jonna M. Frasor, Lalage M. Wakefield, Douglas Ganini, Erich Stauder, Jacek Zielonka, Benjamin N. Gantner, Raul A. Urrutia, David Gius, Marcelo G. Bonini

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

62 Scopus citations

Abstract

Mitochondrial superoxide dismutase (SOD2) suppresses tumor initiation but promotes invasion and dissemination of tumor cells at later stages of the disease. The mechanism of this functional switch remains poorly defined. Our results indicate that as SOD2 expression increases acetylation of lysine 68 ensues. Acetylated SOD2 promotes hypoxic signaling via increased mitochondrial reactive oxygen species (mtROS). mtROS, in turn, stabilize hypoxia-induced factor 2α (HIF2α), a transcription factor upstream of “stemness” genes such as Oct4, Sox2, and Nanog. In this sense, our findings indicate that SOD2^K68Ac and mtROS are linked to stemness reprogramming in breast cancer cells via HIF2α signaling. Based on these findings we propose that, as tumors evolve, the accumulation of SOD2^K68Ac turns on a mitochondrial pathway to stemness that depends on HIF2α and may be relevant for the progression of breast cancer toward poor outcomes.

Original language	English (US)
Pages (from-to)	23534-23541
Number of pages	8
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	47
DOIs	https://doi.org/10.1073/pnas.1902308116
State	Published - 2019
Externally published	Yes

Keywords

Acetylation
Breast cancer
MnSOD
SOD2
Stem cells

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.1902308116

Cite this

He, C., Danes, J. M., Hart, P. C., Zhu, Y., Huang, Y., de Abreu, A. L., O’Brien, J., Mathison, A. J., Tang, B., Frasor, J. M., Wakefield, L. M., Ganini, D., Stauder, E., Zielonka, J., Gantner, B. N., Urrutia, R. A., Gius, D., & Bonini, M. G. (2019). SOD2 acetylation on lysine 68 promotes stem cell reprogramming in breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 116(47), 23534-23541. https://doi.org/10.1073/pnas.1902308116

He, C, Danes, JM, Hart, PC, Zhu, Y, Huang, Y, de Abreu, AL, O’Brien, J, Mathison, AJ, Tang, B, Frasor, JM, Wakefield, LM, Ganini, D, Stauder, E, Zielonka, J, Gantner, BN, Urrutia, RA, Gius, D & Bonini, MG 2019, 'SOD2 acetylation on lysine 68 promotes stem cell reprogramming in breast cancer', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 47, pp. 23534-23541. https://doi.org/10.1073/pnas.1902308116

@article{5fb17dfdeb39427594b68e1b95ecb5c1,

title = "SOD2 acetylation on lysine 68 promotes stem cell reprogramming in breast cancer",

abstract = "Mitochondrial superoxide dismutase (SOD2) suppresses tumor initiation but promotes invasion and dissemination of tumor cells at later stages of the disease. The mechanism of this functional switch remains poorly defined. Our results indicate that as SOD2 expression increases acetylation of lysine 68 ensues. Acetylated SOD2 promotes hypoxic signaling via increased mitochondrial reactive oxygen species (mtROS). mtROS, in turn, stabilize hypoxia-induced factor 2α (HIF2α), a transcription factor upstream of “stemness” genes such as Oct4, Sox2, and Nanog. In this sense, our findings indicate that SOD2K68Ac and mtROS are linked to stemness reprogramming in breast cancer cells via HIF2α signaling. Based on these findings we propose that, as tumors evolve, the accumulation of SOD2K68Ac turns on a mitochondrial pathway to stemness that depends on HIF2α and may be relevant for the progression of breast cancer toward poor outcomes.",

keywords = "Acetylation, Breast cancer, MnSOD, SOD2, Stem cells",

author = "Chenxia He and Danes, {Jeanne M.} and Hart, {Peter C.} and Yueming Zhu and Yunping Huang and {de Abreu}, {Andre Luelsdorf} and Joseph O{\textquoteright}Brien and Mathison, {Angela J.} and Binwu Tang and Frasor, {Jonna M.} and Wakefield, {Lalage M.} and Douglas Ganini and Erich Stauder and Jacek Zielonka and Gantner, {Benjamin N.} and Urrutia, {Raul A.} and David Gius and Bonini, {Marcelo G.}",

year = "2019",

doi = "10.1073/pnas.1902308116",

language = "English (US)",

volume = "116",

pages = "23534--23541",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "47",

}

TY - JOUR

T1 - SOD2 acetylation on lysine 68 promotes stem cell reprogramming in breast cancer

AU - He, Chenxia

AU - Danes, Jeanne M.

AU - Hart, Peter C.

AU - Zhu, Yueming

AU - Huang, Yunping

AU - de Abreu, Andre Luelsdorf

AU - O’Brien, Joseph

AU - Mathison, Angela J.

AU - Tang, Binwu

AU - Frasor, Jonna M.

AU - Wakefield, Lalage M.

AU - Ganini, Douglas

AU - Stauder, Erich

AU - Zielonka, Jacek

AU - Gantner, Benjamin N.

AU - Urrutia, Raul A.

AU - Gius, David

AU - Bonini, Marcelo G.

PY - 2019

Y1 - 2019

N2 - Mitochondrial superoxide dismutase (SOD2) suppresses tumor initiation but promotes invasion and dissemination of tumor cells at later stages of the disease. The mechanism of this functional switch remains poorly defined. Our results indicate that as SOD2 expression increases acetylation of lysine 68 ensues. Acetylated SOD2 promotes hypoxic signaling via increased mitochondrial reactive oxygen species (mtROS). mtROS, in turn, stabilize hypoxia-induced factor 2α (HIF2α), a transcription factor upstream of “stemness” genes such as Oct4, Sox2, and Nanog. In this sense, our findings indicate that SOD2K68Ac and mtROS are linked to stemness reprogramming in breast cancer cells via HIF2α signaling. Based on these findings we propose that, as tumors evolve, the accumulation of SOD2K68Ac turns on a mitochondrial pathway to stemness that depends on HIF2α and may be relevant for the progression of breast cancer toward poor outcomes.

AB - Mitochondrial superoxide dismutase (SOD2) suppresses tumor initiation but promotes invasion and dissemination of tumor cells at later stages of the disease. The mechanism of this functional switch remains poorly defined. Our results indicate that as SOD2 expression increases acetylation of lysine 68 ensues. Acetylated SOD2 promotes hypoxic signaling via increased mitochondrial reactive oxygen species (mtROS). mtROS, in turn, stabilize hypoxia-induced factor 2α (HIF2α), a transcription factor upstream of “stemness” genes such as Oct4, Sox2, and Nanog. In this sense, our findings indicate that SOD2K68Ac and mtROS are linked to stemness reprogramming in breast cancer cells via HIF2α signaling. Based on these findings we propose that, as tumors evolve, the accumulation of SOD2K68Ac turns on a mitochondrial pathway to stemness that depends on HIF2α and may be relevant for the progression of breast cancer toward poor outcomes.

KW - Acetylation

KW - Breast cancer

KW - MnSOD

KW - SOD2

KW - Stem cells

UR - http://www.scopus.com/inward/record.url?scp=85075260452&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075260452&partnerID=8YFLogxK

U2 - 10.1073/pnas.1902308116

DO - 10.1073/pnas.1902308116

M3 - Article

C2 - 31591207

AN - SCOPUS:85075260452

SN - 0027-8424

VL - 116

SP - 23534

EP - 23541

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 47

ER -

SOD2 acetylation on lysine 68 promotes stem cell reprogramming in breast cancer

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this