PUBLICATION

Cohesin mutations are synthetic lethal with stimulation of WNT signaling

Authors
Chin, C.V., Antony, J., Ketharnathan, S., Labudina, A., Gimenez, G., Parsons, K.M., He, J., George, A.J., Pallota, M.M., Musio, A., Braithwaite, A.W., Guilford, P., Hannan, R.D., Horsfield, J.A.
ID
ZDB-PUB-201208-60
Date
2020
Source
eLIFE   9: (Journal)
Registered Authors
Horsfield, Jules, Ketharnathan, Sarada
Keywords
cancer biology, chromosomes, gene expression, human, zebrafish
MeSH Terms
  • Animals
  • Cell Line
  • Cell Division
  • Chromosomal Proteins, Non-Histone/genetics*
  • Zebrafish
  • Synthetic Lethal Mutations/genetics*
  • Humans
  • Carcinogenesis/genetics*
  • Cell Cycle Proteins/genetics*
  • Wnt Signaling Pathway/physiology*
(all 10)
PubMed
33284104 Full text @ Elife
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.
Genes / Markers
Figures
Figure Gallery (19 images) / 2
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
ia5Tg/+chemical treatment by environment: lithium chloride20-25 somites
rad21anz171/nz171; ia5Tg/+chemical treatment by environment: lithium chloride20-25 somites
stag2bnz207/nz207; ia5Tg/+standard conditions20-25 somites
stag2bnz207/nz207; ia5Tg/+standard conditions20-25 somites
stag2bnz207/nz207; ia5Tg/+chemical treatment by environment: lithium chloride20-25 somites
1 - 5 of 5
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ia5TgTransgenic Insertion
    nz171
      		Point Mutation
      nz207
        		Small Deletion
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        No data available
        Fish
        Fish
        ia5Tg/+
        rad21anz171/nz171; ia5Tg/+
        stag2bnz207/nz207; ia5Tg/+
        1 - 3 of 3
        Show
        Antibodies
        No data available
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        mCherryEFGmCherry
        1 - 1 of 1
        Show
        Mapping
        No data available
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        Citation
        Chin, C.V., Antony, J., Ketharnathan, S., Labudina, A., Gimenez, G., Parsons, K.M., He, J., George, A.J., Pallota, M.M., Musio, A., Braithwaite, A.W., Guilford, P., Hannan, R.D., Horsfield, J.A. (2020) Cohesin mutations are synthetic lethal with stimulation of WNT signaling. eLIFE. 9:.