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

Jaewon J. Lee, Robert A.H. van de Ven, Elma Zaganjor, Mei Rosa Ng, Amey Barakat, Joris J.P.G. Demmers, Lydia W.S. Finley, Karina N. Gonzalez Herrera, Yin Pun Hung, Isaac S. Harris, Seung Min Jeong, Gaudenz Danuser, Sandra S. McAllister, Marcia C. Haigis

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7057-7062
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number27
DOIs
StatePublished - Jul 3 2018

Keywords

  • Cancer
  • Cell migration
  • Metabolism
  • Mitochondria
  • SIRT3

ASJC Scopus subject areas

  • General

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    Lee, J. J., van de Ven, R. A. H., Zaganjor, E., Ng, M. R., Barakat, A., Demmers, J. J. P. G., Finley, L. W. S., Gonzalez Herrera, K. N., Hung, Y. P., Harris, I. S., Jeong, S. M., Danuser, G., McAllister, S. S., & Haigis, M. C. (2018). Inhibition of epithelial cell migration and Src/FAK signaling by SIRT3. Proceedings of the National Academy of Sciences of the United States of America, 115(27), 7057-7062. https://doi.org/10.1073/pnas.1800440115