Abstract:
: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.
journal_name
Cancer Celljournal_title
Cancer cellauthors
Ogiwara H,Takahashi K,Sasaki M,Kuroda T,Yoshida H,Watanabe R,Maruyama A,Makinoshima H,Chiwaki F,Sasaki H,Kato T,Okamoto A,Kohno Tdoi
10.1016/j.ccell.2018.12.009subject
Has Abstractpub_date
2019-02-11 00:00:00pages
177-190.e8issue
2eissn
1535-6108issn
1878-3686pii
S1535-6108(18)30581-6journal_volume
35pub_type
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