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Genome-Wide CRISPR Screen Identifies KEAP1 Perturbation as a Vulnerability of ARID1A-Deficient Cells Fournier, Louis-Alexandre; Kalantari, Forouh; Wells, James P.; Lee, Joon Seon; Trigo-Gonzalez, Genny; Moksa, Michelle; Smith, Theodore G.; White, Justin; Shanks, Alynn; Wang, Siyun; Su, Edmund; Wang, Yemin; Huntsman, David G.; Hirst, Martin; Stirling, Peter C.

Abstract

ARID1A is the core DNA-binding subunit of the BAF chromatin remodeling complex and is mutated in about 8% of all cancers. The frequency of ARID1A loss varies between cancer subtypes, with clear cell ovarian carcinoma (CCOC) presenting the highest incidence at > 50% of cases. Despite a growing understanding of the consequences of ARID1A loss in cancer, there remains limited targeted therapeutic options for ARID1A-deficient cancers. Using a genome-wide CRISPR screening approach, we identify KEAP1 as a genetic dependency of ARID1A in CCOC. Depletion or chemical perturbation of KEAP1 results in selective growth inhibition of ARID1A-KO cell lines and edited primary endometrial epithelial cells. While we confirm that KEAP1-NRF2 signalling is dysregulated in ARID1A-KO cells, we suggest that this synthetic lethality is not due to aberrant NRF2 signalling. Rather, we find that KEAP1 perturbation exacerbates genome instability phenotypes associated with ARID1A deficiency. Together, our findings identify a potentially novel synthetic lethal interaction of ARID1A-deficient cells.

Item Metadata

Title
Genome-Wide CRISPR Screen Identifies KEAP1 Perturbation as a Vulnerability of ARID1A-Deficient Cells
Creator
Fournier, Louis-Alexandre; Kalantari, Forouh; Wells, James P.; Lee, Joon Seon; Trigo-Gonzalez, Genny; Moksa, Michelle; Smith, Theodore G.; White, Justin; Shanks, Alynn; Wang, Siyun; Su, Edmund; Wang, Yemin; Huntsman, David G.; Hirst, Martin; Stirling, Peter C.
Contributor
BC Cancer Research Centre. Terry Fox Laboratory; BC Cancer Research Centre. Molecular Oncology; Michael Smith Laboratories
Publisher
Multidisciplinary Digital Publishing Institute
Date Issued
2024-08-24
Description
ARID1A is the core DNA-binding subunit of the BAF chromatin remodeling complex and is mutated in about 8% of all cancers. The frequency of ARID1A loss varies between cancer subtypes, with clear cell ovarian carcinoma (CCOC) presenting the highest incidence at > 50% of cases. Despite a growing understanding of the consequences of ARID1A loss in cancer, there remains limited targeted therapeutic options for ARID1A-deficient cancers. Using a genome-wide CRISPR screening approach, we identify KEAP1 as a genetic dependency of ARID1A in CCOC. Depletion or chemical perturbation of KEAP1 results in selective growth inhibition of ARID1A-KO cell lines and edited primary endometrial epithelial cells. While we confirm that KEAP1-NRF2 signalling is dysregulated in ARID1A-KO cells, we suggest that this synthetic lethality is not due to aberrant NRF2 signalling. Rather, we find that KEAP1 perturbation exacerbates genome instability phenotypes associated with ARID1A deficiency. Together, our findings identify a potentially novel synthetic lethal interaction of ARID1A-deficient cells.
Subject
ARID1A; KEAP1; CRISPR screening; synthetic lethality
Genre
Article
Type
Text
Language
eng
Date Available
2024-09-20
Provider
Vancouver : University of British Columbia Library
Rights
CC BY 4.0
DOI
10.14288/1.0445423
URI
http://hdl.handle.net/2429/89272
Affiliation
Medicine, Faculty of; Medical Genetics, Department of; Obstetrics and Gynaecology, Department of; Pathology and Laboratory Medicine, Department of
Citation
Cancers 16 (17): 2949 (2024)
Publisher DOI
10.3390/cancers16172949
Peer Review Status
Reviewed
Scholarly Level
Faculty; Researcher
Rights URI
https://creativecommons.org/licenses/by/4.0/
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CC BY 4.0