1. Therapeutic targeting of ARID1A-deficient cancer cells with RITA (Reactivating p53 and inducing tumor apoptosis).
- Author
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Wang Z, Zhang X, Luo Y, Song Y, Xiang C, He Y, Wang K, Yu Y, Wang Z, Peng W, Ding Y, Liu S, and Wu C
- Subjects
- Humans, Cell Line, Tumor, DNA Damage, Animals, Mice, HCT116 Cells, Apoptosis Regulatory Proteins metabolism, Apoptosis Regulatory Proteins genetics, Proto-Oncogene Proteins c-mdm2 metabolism, Proto-Oncogene Proteins c-mdm2 genetics, Mice, Nude, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Cyclin-Dependent Kinase Inhibitor p21 genetics, Furans, Proto-Oncogene Proteins, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 deficiency, Apoptosis drug effects, Transcription Factors metabolism, Transcription Factors genetics, DNA-Binding Proteins metabolism, DNA-Binding Proteins genetics, Colorectal Neoplasms metabolism, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Colorectal Neoplasms drug therapy
- Abstract
ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is frequently mutated in various cancer types and has emerged as a potential therapeutic target. In this study, we observed that ARID1A-deficient colorectal cancer (CRC) cells showed synthetic lethal effects with a p53 activator, RITA (reactivating p53 and inducing tumor apoptosis). RITA, an inhibitor of the p53-MDM2 interaction, exhibits increased sensitivity in ARID1A-deficient cells compared to ARID1A wild-type cells. Mechanistically, the observed synthetic lethality is dependent on both p53 activation and DNA damage accumulation, which are regulated by the interplay between ARID1A and RITA. ARID1A loss exhibits an opposing effect on p53 targets, leading to decreased p21 expression and increased levels of proapoptotic genes, PUMA and NOXA, which is further potentiated by RITA treatment, ultimately inducing cell apoptosis. Meanwhile, ARID1A loss aggravates RITA-induced DNA damage accumulation by downregulating Chk2 phosphorylation. Taken together, ARID1A loss significantly heightens sensitivity to RITA in CRC, revealing a novel synthetic lethal interaction between ARID1A and RITA. These findings present a promising therapeutic approach for colorectal cancer characterized by ARID1A loss-of-function mutations., (© 2024. The Author(s).)
- Published
- 2024
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