Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts

Author:

van der Lelij Petra1,Lieb Simone2,Jude Julian1ORCID,Wutz Gordana1,Santos Catarina P34,Falkenberg Katrina1,Schlattl Andreas2,Ban Jozef5,Schwentner Raphaela5ORCID,Hoffmann Thomas1,Kovar Heinrich56,Real Francisco X347,Waldman Todd8,Pearson Mark A2,Kraut Norbert2,Peters Jan-Michael1,Zuber Johannes1ORCID,Petronczki Mark2ORCID

Affiliation:

1. Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria

2. Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

3. Spanish National Cancer Research Centre, Madrid, Spain

4. Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain

5. Children’s Cancer Research Institute, Vienna, Austria

6. Department for Pediatrics, Medical University of Vienna, Vienna, Austria

7. Department de Ciències Experimentals I de la Salut, Universitat Pompeu Fabra, Barcelona, Spain

8. Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington DC, United States

Abstract

Recent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 support sister chromatid cohesion to redundantly ensure cell survival. STAG1 represents a vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2 across different cancer contexts. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics.

Funder

Austrian Science Fund

Österreichische Forschungsförderungsgesellschaft

European Research Council

Fundación Científica Asociación Española Contra el Cáncer

National Institutes of Health

Alex's Lemonade Stand Foundation for Childhood Cancer

Boehringer Ingelheim

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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