@article{9473809f4f884e72a801e6ff49289399,
title = "Inhibition of epithelial cell migration and Src/FAK signaling by SIRT3",
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 = "Cancer, Cell migration, Metabolism, Mitochondria, SIRT3",
author = "Lee, {Jaewon J.} and {van de Ven}, {Robert A.H.} and Elma Zaganjor and Ng, {Mei Rosa} and Amey Barakat and Demmers, {Joris J.P.G.} and Finley, {Lydia W.S.} and {Gonzalez Herrera}, {Karina N.} and Hung, {Yin Pun} and Harris, {Isaac S.} and Jeong, {Seung Min} and Gaudenz Danuser and McAllister, {Sandra S.} and Haigis, {Marcia C.}",
note = "Funding Information: We thank Joan Massagu{\'e} (Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center) and Paola Chiarugi (University of Florence) for providing reagents. We also thank members of the M.C.H., G.D., Brugge, and S.S.M. laboratories for helpful discussions and technical assistance, especially F. Kyle Satterstrom for analysis of SIRT3 expression. We thank the Nikon Imaging Center at Harvard Medical School for help with microscopy. Analyses of cell migration assays were performed on the Orchestra cluster supported by the Harvard Medical School Research Information Technology Group. J.J.L. was supported as a Howard Hughes Medical Institute Medical Research Fellow. E.Z. was supported by the American Heart Association (Award 15POST25560077). M.C.H. is supported by National Institutes of Health Grant R01DK103295 from the National Institute of Diabetes and Digestive and Kidney Diseases, Grant R01CA213062 from the National Cancer Institute, the Ludwig Center at Harvard, and the Glenn Foundation for Medical Research. Funding Information: ACKNOWLEDGMENTS. We thank Joan Massagu{\'e} (Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center) and Paola Chiarugi (University of Florence) for providing reagents. We also thank members of the M.C.H., G.D., Brugge, and S.S.M. laboratories for helpful discussions and technical assistance, especially F. Kyle Satterstrom for analysis of SIRT3 expression. We thank the Nikon Imaging Center at Harvard Medical School for help with microscopy. Analyses of cell migration assays were performed on the Orchestra cluster supported by the Harvard Medical School Research Information Technology Group. J.J.L. was supported as a Howard Hughes Medical Institute Medical Research Fellow. E.Z. was supported by the American Heart Association (Award 15POST25560077). M.C.H. is supported by National Institutes of Health Grant R01DK103295 from the National Institute of Diabetes and Digestive and Kidney Diseases, Grant R01CA213062 from the National Cancer Institute, the Ludwig Center at Harvard, and the Glenn Foundation for Medical Research. Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All Rights Reserved.",
year = "2018",
month = jul,
day = "3",
doi = "10.1073/pnas.1800440115",
language = "English (US)",
volume = "115",
pages = "7057--7062",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "27",
}