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Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy [ChIP-Seq]

ABSTRACT: Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified 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, our 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. Utilizing this unique vulnerability of Arid1a mutated GC cells, our combinatorial treatment with an epigenetic inhibitor and a p53 agonist selectively inhibited Arid1a heterozygous tumor growth, providing a novel therapeutic option for GC.

ORGANISM(S): Mus musculus

PROVIDER: GSE144385 | GEO | 2021/03/16

REPOSITORIES: GEO

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