1. Cancer Biology
  2. Chromosomes and Gene Expression
Download icon

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
Research Article
  • Cited 6
  • Views 1,918
  • Annotations
Cite this article as: eLife 2020;9:e61405 doi: 10.7554/eLife.61405

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.

Metrics

  • 1,918
    Page views
  • 272
    Downloads
  • 6
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    2. Ecology
    Daniel Garcia-Souto et al.
    Short Report

    Clonally transmissible cancers are tumour lineages that are transmitted between individuals via the transfer of living cancer cells. In marine bivalves, leukaemia-like transmissible cancers, called hemic neoplasia (HN), have demonstrated the ability to infect individuals from different species. We performed whole-genome sequencing in eight warty venus clams that were diagnosed with HN, from two sampling points located more than 1000 nautical miles away in the Atlantic Ocean and the Mediterranean Sea Coasts of Spain. Mitochondrial genome sequencing analysis from neoplastic animals revealed the coexistence of haplotypes from two different clam species. Phylogenies estimated from mitochondrial and nuclear markers confirmed this leukaemia originated in striped venus clams and later transmitted to clams of the species warty venus, in which it survives as a contagious cancer. The analysis of mitochondrial and nuclear gene sequences supports all studied tumours belong to a single neoplastic lineage that spreads in the Seas of Southern Europe.

    1. Cancer Biology
    2. Cell Biology
    Alejandro La Greca et al.
    Research Article

    Estrogen (E2) and Progesterone (Pg), via their specific receptors (ERalpha and PR), are major determinants in the development and progression of endometrial carcinomas, However, their precise mechanism of action and the role of other transcription factors involved are not entirely clear. Using Ishikawa endometrial cancer cells, we report that E2 treatment exposes a set of progestin-dependent PR binding sites which include both E2 and progestin target genes. ChIP-seq results from hormone-treated cells revealed a non-random distribution of PAX2 binding in the vicinity of these estrogen-promoted PR sites. Altered expression of hormone regulated genes in PAX2 knockdown cells suggests a role for PAX2 in fine-tuning ERalpha and PR interplay in transcriptional regulation. Analysis of long-range interactions by Hi-C coupled with ATAC-seq data showed that these regions, that we call 'progestin control regions' (PgCRs), exhibited an open chromatin state even before hormone exposure and were non-randomly associated with regulated genes. Nearly 20% of genes potentially influenced by PgCRs were found to be altered during progression of endometrial cancer. Our findings suggest that endometrial response to progestins in differentiated endometrial tumor cells results in part from binding of PR together with PAX2 to accessible chromatin regions. What maintains these regions open remains to be studied.