Cohesin mutations are synthetic lethal with stimulation of WNT signaling
- University of Otago, New Zealand
- Australian National University, Australia
- 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.
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Expression profiling in cohesin mutant MCF10A epithelial and CMK leukaemia cellsNCBI Gene Expression Omnibus, GSE154086.
Article and author information
Author details
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
- Ravi Majeti, Stanford University, United States
Publication history
- Received: July 24, 2020
- Accepted: December 4, 2020
- Accepted Manuscript published: December 7, 2020 (version 1)
- 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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Cohesin mutations are synthetic lethal with stimulation of WNT signaling
eLife 9:e61405.
https://doi.org/10.7554/eLife.61405
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