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Proc Natl Acad Sci U S A. 2018 Jul 3;115(27):7057-7062. doi: 10.1073/pnas.1800440115. Epub 2018 Jun 18.

Inhibition of epithelial cell migration and Src/FAK signaling by SIRT3.

Author information

1
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
2
Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115.
3
Hematology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
4
Department of Medicine, Harvard Medical School, Boston, MA 02115.
5
Broad Institute of Harvard and MIT, Cambridge, MA 02141.
6
Harvard Stem Cell Institute, Cambridge, MA 02138.
7
Department of Cell Biology, Harvard Medical School, Boston, MA 02115; marcia_haigis@hms.harvard.edu.

Abstract

Metastasis remains the leading cause of cancer mortality, and reactive oxygen species (ROS) signaling promotes the metastatic cascade. However, the molecular pathways that control ROS signaling relevant to metastasis are little studied. Here, we identify SIRT3, a mitochondrial deacetylase, as a regulator of cell migration via its control of ROS signaling. We find that, although mitochondria are present at the leading edge of migrating cells, SIRT3 expression is down-regulated during migration, resulting in elevated ROS levels. This SIRT3-mediated control of ROS represses Src oxidation and attenuates focal adhesion kinase (FAK) activation. SIRT3 overexpression inhibits migration and metastasis in breast cancer cells. Finally, in human breast cancers, SIRT3 expression is inversely correlated with metastatic outcome and Src/FAK signaling. Our results reveal a role for SIRT3 in cell migration, with important implications for breast cancer progression.

KEYWORDS:

SIRT3; cancer; cell migration; metabolism; mitochondria

PMID:
29915029
PMCID:
PMC6142214
DOI:
10.1073/pnas.1800440115
[Indexed for MEDLINE]
Free PMC Article

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