ARID1A型
癌变
生物
癌症研究
表观遗传学
癌症
染色质
染色质重塑
增强子
杂合子丢失
基因
遗传学
突变
基因表达
等位基因
作者
Adrian Kwan Ho Loe,Roshane Francis,Jieun Seo,Du Li,Yunshan Wang,Jieun Kim,Shaheed W. Hakim,Jung-Eun Kim,Housheng Hansen He,Haiyang Guo,Tae-Hee Kim
摘要
Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified AT-rich interaction domain 1A (ARID1A), a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, mouse genetic and single-cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage-dependent roles. Using this unique vulnerability of Arid1a mutated GC cells, our combined treatment with the epigenetic inhibitor, TP064, and the p53 agonist, Nutlin-3, inhibited growth of Arid1a heterozygous tumor organoids, providing a novel therapeutic option for GC.
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