Journal
CANCER CELL
Volume 35, Issue 2, Pages 177-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.12.009
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [JP22131006]
- Japan Society for the Promotion of Science [JP26830122, JP17K11310]
- Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development [JP17ck0106168, JP17ck0106374, JP18ck0106374]
- National Cancer Center Research and Development Fund
- Yamagata Prefectural Government
- city of Tsuruoka
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ARID1A encodes an SWI/SNF chromatin-remodeling factor and is frequently mutated in various cancers. This study demonstrates that ARID1A-deficient cancer cells are specifically vulnerable to inhibition of the antioxidant glutathione (GSH) and the glutamate-cysteine ligase synthetase catalytic subunit (GCLC), a rate-limiting enzyme for GSH synthesis. Inhibition of GCLC markedly decreased GSH in ARID1A-deficient cancer cells, leading to apoptotic cell death triggered by excessive amounts of reactive oxygen species. The vulnerability of ARID1A-deficient cancer cells results from low basal levels of GSH due to impaired expression of SLC7A11. The SLC7A11-encoded cystine transporter supplies cells with cysteine, a key source of GSH, and its expression is enhanced by ARID1A-mediated chromatin remodeling. Thus, ARID1A-deficient cancers are susceptible to synthetic lethal targeting of GCLC.
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