文章：

全基因组CRISPR筛选揭示KEAP1扰动是ARID1A缺陷细胞的易损性

Genome-Wide CRISPR Screen Identifies KEAP1 Perturbation as a Vulnerability of ARID1A-Deficient Cells

原文发布日期：24 August 2024

DOI: 10.3390/cancers16172949

类型: Article

开放获取: 是

英文摘要：

ARID1A is the core DNA-binding subunit of the BAF chromatin remodeling complex and is mutated in about 8% of all cancers. The frequency of ARID1A loss varies between cancer subtypes, with clear cell ovarian carcinoma (CCOC) presenting the highest incidence at > 50% of cases. Despite a growing understanding of the consequences of ARID1A loss in cancer, there remains limited targeted therapeutic options for ARID1A-deficient cancers. Using a genome-wide CRISPR screening approach, we identify KEAP1 as a genetic dependency of ARID1A in CCOC. Depletion or chemical perturbation of KEAP1 results in selective growth inhibition of ARID1A-KO cell lines and edited primary endometrial epithelial cells. While we confirm that KEAP1-NRF2 signalling is dysregulated in ARID1A-KO cells, we suggest that this synthetic lethality is not due to aberrant NRF2 signalling. Rather, we find that KEAP1 perturbation exacerbates genome instability phenotypes associated with ARID1A deficiency. Together, our findings identify a potentially novel synthetic lethal interaction of ARID1A-deficient cells.

摘要翻译： 

ARID1A是BAF染色质重塑复合体的核心DNA结合亚基，在所有癌症中约有8%发生突变。ARID1A缺失频率因癌症亚型而异，其中透明细胞卵巢癌的发生率最高，超过50%的病例存在该基因缺失。尽管对ARID1A缺失在癌症中影响的认识日益深入，针对ARID1A缺陷型癌症的靶向治疗方案仍然有限。通过全基因组CRISPR筛选方法，我们发现KEAP1是透明细胞卵巢癌中ARID1A的遗传依赖性靶点。KEAP1的敲除或化学扰动可选择性抑制ARID1A敲除细胞系及编辑后的原代子宫内膜上皮细胞的生长。虽然我们证实KEAP1-NRF2信号通路在ARID1A敲除细胞中失调，但研究显示这种合成致死效应并非由异常的NRF2信号传导引起。相反，我们发现KEAP1扰动会加剧与ARID1A缺陷相关的基因组不稳定性表型。综上，本研究揭示了ARID1A缺陷型细胞中一种潜在的新型合成致死相互作用机制。

原文链接：

Genome-Wide CRISPR Screen Identifies KEAP1 Perturbation as a Vulnerability of ARID1A-Deficient Cells