Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts

  1. Petra van der Lelij
  2. Simone Lieb
  3. Julian Jude
  4. Gordana Wutz
  5. Catarina P Santos
  6. Katrina Falkenberg
  7. Andreas Schlattl
  8. Jozef Ban
  9. Raphaela Schwentner
  10. Thomas Hoffmann
  11. Heinrich Kovar
  12. Francisco X Real
  13. Todd Waldman
  14. Mark A Pearson
  15. Norbert Kraut
  16. Jan-Michael Peters
  17. Johannes Zuber
  18. Mark Petronczki  Is a corresponding author
  1. Research Institute of Molecular Pathology, Austria
  2. Boehringer Ingelheim RCV, Austria
  3. Research Institute of Molecular Pathology, Austria
  4. Spanish National Cancer Research Centre, Spain
  5. Children's Cancer Research Institute, Austria
  6. 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

The following previously published data sets were used

Article and author information

Author details

  1. Petra van der Lelij

    Research Institute of Molecular Pathology, Vienna, Austria
    Competing interests
    No competing interests declared.
  2. Simone Lieb

    Boehringer Ingelheim RCV, Vienna, Austria
    Competing interests
    Simone Lieb, Simone Lieb is a full-time employee of Boehringer Ingelheim RCV..
  3. Julian Jude

    Research Institute of Molecular Pathology, Vienna, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9091-9867
  4. Gordana Wutz

    Research Institute of Molecular Pathology, Vienna, Austria
    Competing interests
    No competing interests declared.
  5. Catarina P Santos

    Spanish National Cancer Research Centre, Madrid, Spain
    Competing interests
    No competing interests declared.
  6. Katrina Falkenberg

    Research Institute of Molecular Pathology, Vienna, Austria
    Competing interests
    No competing interests declared.
  7. Andreas Schlattl

    Boehringer Ingelheim RCV, Vienna, Austria
    Competing interests
    Andreas Schlattl, Andreas Schlattl is a full-time employee of Boehringer Ingelheim RCV..
  8. Jozef Ban

    Children's Cancer Research Institute, Vienna, Austria
    Competing interests
    No competing interests declared.
  9. Raphaela Schwentner

    Children's Cancer Research Institute, Vienna, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6839-0322
  10. Thomas Hoffmann

    Research Institute of Molecular Pathology, Vienna, Austria
    Competing interests
    No competing interests declared.
  11. Heinrich Kovar

    Children's Cancer Research Institute, Vienna, Austria
    Competing interests
    No competing interests declared.
  12. Francisco X Real

    Spanish National Cancer Research Centre, Madrid, Spain
    Competing interests
    No competing interests declared.
  13. Todd Waldman

    Lombardi Comprehensive Cancer center, Georgetown University School of Medicine, Washington, United States
    Competing interests
    No competing interests declared.
  14. Mark A Pearson

    Boehringer Ingelheim RCV, Vienna, Austria
    Competing interests
    Mark A Pearson, Mark Pearson is a full-time employee of Boehringer Ingelheim RCV..
  15. Norbert Kraut

    Boehringer Ingelheim RCV, Vienna, Austria
    Competing interests
    Norbert Kraut, Norbert Kraut is a full-time employee of Boehringer Ingelheim RCV..
  16. Jan-Michael Peters

    Research Institute of Molecular Pathology, Vienna, Austria
    Competing interests
    No competing interests declared.
  17. Johannes Zuber

    Research Institute of Molecular Pathology, Vienna, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8810-6835
  18. Mark Petronczki

    Boehringer Ingelheim RCV, Vienna, Austria
    For correspondence
    mark_paul.petronczki@boehringer-ingelheim.com
    Competing interests
    Mark Petronczki, Full-time employee of Boehringer Ingelheim RCV.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0139-5692

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

  1. Andrea Musacchio, Max Planck Institute of Molecular Physiology, Germany

Publication history

  1. Received: March 19, 2017
  2. Accepted: July 3, 2017
  3. Accepted Manuscript published: July 10, 2017 (version 1)
  4. Accepted Manuscript updated: July 13, 2017 (version 2)
  5. 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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  1. Petra van der Lelij
  2. Simone Lieb
  3. Julian Jude
  4. Gordana Wutz
  5. Catarina P Santos
  6. Katrina Falkenberg
  7. Andreas Schlattl
  8. Jozef Ban
  9. Raphaela Schwentner
  10. Thomas Hoffmann
  11. Heinrich Kovar
  12. Francisco X Real
  13. Todd Waldman
  14. Mark A Pearson
  15. Norbert Kraut
  16. Jan-Michael Peters
  17. Johannes Zuber
  18. Mark Petronczki
(2017)
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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