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Genome-wide CRISPR-Cas9 screen reveals selective vulnerability of ARID1A deficiency Hepatocellular Carcinoma

ABSTRACT: To uncover therapeutic strategies for ARID1A deficient HCC, we performed genome-scale CRISPR–Cas9 based synthetic lethality screens using ARID1A deficiency HCC cellular model

ORGANISM(S): Homo sapiens

PROVIDER: GSE228177 | GEO | 2023/09/11

REPOSITORIES: GEO

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Genome-wide CRISPR-Cas9 screen reveals selective vulnerability of ARID1A deficiency Hepatocellular Carcinoma

Project description:Genome-wide CRISPR-Cas9 screen reveals selective vulnerability of ARID1A deficiency Hepatocellular Carcinoma

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Targeting EZH2 methyltransferase activity in ARID1A mutated cells as a synthetic lethal therapeutic strategy

Project description:ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration. Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.

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Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies [ATAC-Seq]

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