Cohesin mutations are synthetic lethal with stimulation of WNT signaling
| Autor: | Jin-Shu He, Antony W. Braithwaite, Ross D. Hannan, Antonio Musio, Kate M Parsons, Parry Guilford, Jisha Antony, Amee J George, Julia A. Horsfield, Anastasia Labudina, Gregory Gimenez, Sarada Ketharnathan, Chue Vin Chin, Maria Michela Pallotta |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cohesin complex Carcinogenesis Chromosomal Proteins Non-Histone QH301-705.5 Science Mutant cohesin Cell Cycle Proteins Synthetic lethality Biology medicine.disease_cause drug screen General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Biology (General) Wnt Signaling Pathway Zebrafish Cancer Biology General Immunology and Microbiology Cohesin General Neuroscience Wnt signaling pathway wnt signaling General Medicine Cell cycle Chromosomes and Gene Expression biology.organism_classification Cell biology 030104 developmental biology synthetic lethal 030220 oncology & carcinogenesis Medicine biological phenomena cell phenomena and immunity Synthetic Lethal Mutations transcription Cell Division Research Article Human |
| Zdroj: | eLife, Vol 9 (2020) eLife |
| ISSN: | 2050-084X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|