Cohesin mutations are synthetic lethal with stimulation of WNT signaling
Chue Vin Chin,
Jisha Antony,
Sarada Ketharnathan,
Anastasia Labudina,
Gregory Gimenez,
Kate M Parsons,
Jinshu He,
Amee J George,
Maria Michela Pallotta,
Antonio Musio,
Antony Braithwaite,
Parry Guilford,
Ross D Hannan,
Julia A Horsfield
Affiliations
Chue Vin Chin
Department of Pathology, Otago Medical School, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand; Genetics Otago Research Centre, University of Otago, Dunedin, New Zealand
Jisha Antony
Department of Pathology, Otago Medical School, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand; Genetics Otago Research Centre, University of Otago, Dunedin, New Zealand
Sarada Ketharnathan
Department of Pathology, Otago Medical School, University of Otago, Dunedin, New Zealand; Genetics Otago Research Centre, University of Otago, Dunedin, New Zealand
Anastasia Labudina
Department of Pathology, Otago Medical School, University of Otago, Dunedin, New Zealand; Genetics Otago Research Centre, University of Otago, Dunedin, New Zealand
Gregory Gimenez
Department of Pathology, Otago Medical School, University of Otago, Dunedin, New Zealand; Genetics Otago Research Centre, University of Otago, Dunedin, New Zealand
Kate M Parsons
The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
Jinshu He
The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Pisa, Italy
Antony Braithwaite
Department of Pathology, Otago Medical School, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
Parry Guilford
Department of Biochemistry, University of Otago, Dunedin, New Zealand
Ross D Hannan
The John Curtin School of Medical Research, The Australian National University, Canberra, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia; School of Biomedical Sciences, University of Queensland, St Lucia, Australia
Department of Pathology, Otago Medical School, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand; Genetics Otago Research Centre, University of Otago, Dunedin, New Zealand
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 3009 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 β-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.
