Cohesin mutations are synthetic lethal with stimulation of WNT signaling

  1. Chue Vin Chin
  2. Jisha Antony
  3. Sarada Ketharnathan
  4. Anastasia Labudina
  5. Gregory Gimenez
  6. Kate M Parsons
  7. Jinshu He
  8. Amee J George
  9. Maria Michela Pallota
  10. Antonio Musio
  11. Antony W Braithwaite
  12. Parry Guilford
  13. Ross D Hannan
  14. Julia A Horsfield  Is a corresponding author
  1. University of Otago, New Zealand
  2. Australian National University, Australia
  3. Consiglio Nazionale delle Ricerche (CNR), Italy

Abstract

Mutations in genes encoding subunits of the cohesin complex are common in several cancers, but may also expose druggable vulnerabilities. We generated isogenic MCF10A cell lines with deletion mutations of genes encoding cohesin subunits SMC3, RAD21 and STAG2 and screened for synthetic lethality with 3,009 FDA-approved compounds. The screen identified several compounds that interfere with transcription, DNA damage repair and the cell cycle. Unexpectedly, one of the top 'hits' was a GSK3 inhibitor, an agonist of Wnt signaling. We show that sensitivity to GSK3 inhibition is likely due to stabilization of b-catenin in cohesin mutant cells, and that Wnt-responsive gene expression is highly sensitized in STAG2-mutant CMK leukemia cells. Moreover, Wnt activity is enhanced in zebrafish mutant for cohesin subunits stag2b and rad21. Our results suggest that cohesin mutations could progress oncogenesis by enhancing Wnt signaling, and that targeting the Wnt pathway may represent a novel therapeutic strategy for cohesin mutant cancers.

Data availability

All RNA sequencing data has been deposited at the GEO database under accession codes GSE154086. All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-5 and Table 1.

The following data sets were generated

Article and author information

Author details

  1. Chue Vin Chin

    Department of Pathology, University of Otago, Dunedin, New Zealand
    Competing interests
    The authors declare that no competing interests exist.
  2. Jisha Antony

    Pathology, University of Otago, Dunedin, New Zealand
    Competing interests
    The authors declare that no competing interests exist.
  3. Sarada Ketharnathan

    Department of Pathology, University of Otago, Dunedin, New Zealand
    Competing interests
    The authors declare that no competing interests exist.
  4. Anastasia Labudina

    Department of Pathology, University of Otago, Dunedin, New Zealand
    Competing interests
    The authors declare that no competing interests exist.
  5. Gregory Gimenez

    Department of Pathology, University of Otago, Dunedin, New Zealand
    Competing interests
    The authors declare that no competing interests exist.
  6. Kate M Parsons

    The John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Jinshu He

    The John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Amee J George

    The John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0265-4476
  9. Maria Michela Pallota

    Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Pisa, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. Antonio Musio

    Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Pisa, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7701-6543
  11. Antony W Braithwaite

    Pathology, University of Otago, Dunedin, New Zealand
    Competing interests
    The authors declare that no competing interests exist.
  12. Parry Guilford

    Department of Biochemistry, University of Otago, Dunedin, New Zealand
    Competing interests
    The authors declare that no competing interests exist.
  13. Ross D Hannan

    The John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  14. Julia A Horsfield

    Department of Pathology, University of Otago, Dunedin, New Zealand
    For correspondence
    julia.horsfield@otago.ac.nz
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9536-7790

Funding

Health Research Council of New Zealand (15/229)

  • Julia A Horsfield

Health Research Council of New Zealand (19/415)

  • Ross D Hannan
  • Julia A Horsfield

Associazione Italiana per la Ricerca sul Cancro (IG23284)

  • Antonio Musio

The Maurice Wilkins centre for Molecular Biodiscovery (3705733)

  • Jisha Antony
  • Julia A Horsfield

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Work with zebrafish was approved by the University of Otago (Dunedin) Animal Ethics Committee (AUP19/17) and conducted using approved institutional animal care standard operating procedures.

Reviewing Editor

  1. Ravi Majeti, Stanford University, United States

Publication history

  1. Received: July 24, 2020
  2. Accepted: December 4, 2020
  3. Accepted Manuscript published: December 7, 2020 (version 1)
  4. Version of Record published: December 17, 2020 (version 2)

Copyright

© 2020, Chin 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. Chue Vin Chin
  2. Jisha Antony
  3. Sarada Ketharnathan
  4. Anastasia Labudina
  5. Gregory Gimenez
  6. Kate M Parsons
  7. Jinshu He
  8. Amee J George
  9. Maria Michela Pallota
  10. Antonio Musio
  11. Antony W Braithwaite
  12. Parry Guilford
  13. Ross D Hannan
  14. Julia A Horsfield
(2020)
Cohesin mutations are synthetic lethal with stimulation of WNT signaling
eLife 9:e61405.
https://doi.org/10.7554/eLife.61405

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