Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts
- Research Institute of Molecular Pathology, Austria
- Boehringer Ingelheim RCV, Austria
- Research Institute of Molecular Pathology, Austria
- Spanish National Cancer Research Centre, Spain
- Children's Cancer Research Institute, Austria
- Georgetown University School of Medicine, United States
Abstract
Recent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 support sister chromatid cohesion to redundantly ensure cell survival. STAG1 represents a vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2 across different cancer contexts. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics.
Data availability
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The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics dataPublically available via the cBioPortal github.
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Toil enables reproducible, open source, big biomedical data analysesPublically available via the UCSC Xena data hub.
Article and author information
Author details
Raphaela Schwentner
Funding
Austrian Science Fund (SFB-F34)
- Jan-Michael Peters
National Institutes of Health (R01CA169345)
- Todd Waldman
Innovation Grant from Alex's Lemonade Stand
- Todd Waldman
Boehringer Ingelheim RCV
- Simone Lieb
- Andreas Schlattl
- Mark A Pearson
- Norbert Kraut
- Mark Petronczki
Austrian Science Fund (Wittgenstein award Z196-B20)
- Jan-Michael Peters
Austrian Research Promotion Agency (FFG-834223)
- Jan-Michael Peters
Austrian Research Promotion Agency (FFG-852936)
- Jan-Michael Peters
Austrian Research Promotion Agency (FFG-840283)
- Jan-Michael Peters
European Research Council (ERC no. 336860)
- Johannes Zuber
Austrian Science Fund (SFB grant F4710)
- Johannes Zuber
Austrian Science Fund (ERA-Net grant I 1225-B19)
- Heinrich Kovar
Fundación Científica Asociación Española Contra el Cancer
- Francisco X Real
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Andrea Musacchio, Max Planck Institute of Molecular Physiology, Germany
Version history
- Received: March 19, 2017
- Accepted: July 3, 2017
- Accepted Manuscript published: July 10, 2017 (version 1)
- Accepted Manuscript updated: July 13, 2017 (version 2)
- Version of Record published: July 27, 2017 (version 3)
Copyright
© 2017, van der Lelij et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts
eLife 6:e26980.
https://doi.org/10.7554/eLife.26980
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