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

doi:10.1073/pnas.1800440115

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

Journal article

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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, …

Proceedings of the National Academy of Sciences - PNAS, Vol.115(27), pp.7057-7062

07/03/2018

DOI: 10.1073/pnas.1800440115

PMID: 29915029

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Abstract

SignificanceMetastasis is the most common cause of cancer-related death. The function of reactive oxygen species (ROS) in metastasis is conflicting, and it has been observed to promote or inhibit metastasis. Thus, a more in-depth analysis is needed to assess the impact of ROS on metastasis. In this study, we find that local down-regulation of SIRT3 at the leading edge of migrating cells results in elevated ROS levels and activation of Src/focal adhesion kinase signaling. Further, collective cell migration and metastases formation are inhibited by SIRT3, while patient data sets point to an inverse correlation between SIRT3 and breast cancer metastasis. 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.

Biological Sciences

Cell Biology

Details

Title: Subtitle: Inhibition of epithelial cell migration and Src/FAK signaling by SIRT3
Creators: Jaewon J. Lee - Harvard University
Robert A. H. van de Ven - Harvard University
Elma Zaganjor - Harvard University
Mei Rosa Ng - Harvard University
Amey Barakat - Brigham and Women's Hospital
Joris J. P. G. Demmers - Harvard University
Lydia W. S. Finley - Harvard University
Karina N. Gonzalez Herrera - Harvard Medical School
Yin Pun Hung - Harvard University
Isaac S. Harris - Harvard University
Seung Min Jeong - Harvard University
Gaudenz Danuser - Harvard University
Sandra S. McAllister - Broad Institute
Marcia C. Haigis - Harvard University
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.115(27), pp.7057-7062
DOI: 10.1073/pnas.1800440115
PMID: 29915029
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Number of pages: 6
Language: English
Date published: 07/03/2018
Academic Unit: Surgery
Record Identifier: 9985240988002771

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