Therapeutic targeting of ARID1A-deficient cancer cells with RITA (Reactivating p53 and inducing tumor apoptosis).
Zihuan WangXu ZhangYuchen LuoYijiang SongCheng XiangYilin HeKejin WangYingnan YuZhen WangWenxuan PengYi DingSi-de LiuChangjie WuPublished in: Cell death & disease (2024)
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.
Keyphrases
- dna damage
- cell cycle arrest
- induced apoptosis
- oxidative stress
- wild type
- endoplasmic reticulum stress
- cell proliferation
- gene expression
- squamous cell carcinoma
- poor prognosis
- genome wide
- immune response
- risk assessment
- dna repair
- dna methylation
- endothelial cells
- toll like receptor
- inflammatory response
- high glucose
- cancer therapy
- lymph node metastasis