Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China.
Department of Oncology, Peking University International Hospital, Beijing 102206, China.
Cell Rep Med. 2023 Nov 21;4(11):101264. doi: 10.1016/j.xcrm.2023.101264. Epub 2023 Nov 7.
ARID1A is among the most commonly mutated tumor suppressor genes in hepatocellular carcinoma (HCC). In this study, we conduct a CRISPR-Cas9 synthetic lethality screen using ARID1A-deficient HCC cells to identify approaches to treat HCC patients harboring ARID1A deficiency. This strategy reveals that the survival of these ARID1A-deficient HCC cells is highly dependent on genes related to the tricarboxylic acid (TCA) cycle. Mechanistically, ARID1A loss represses expression of key glycolysis-related gene PKM, shifting cellular glucose metabolism from aerobic glycolysis to dependence on the TCA cycle and oxidative phosphorylation. Cuproptosis is a recently defined form of copper-induced cell death reported to directly target the TCA cycle. Here, we find that ARID1A-deficient HCC cells and xenograft tumors are highly sensitive to copper treatment. Together, these results offer evidence of the synthetic lethality between ARID1A deficiency and mitochondrial respiration impairment, suggesting that copper treatment constitutes a promising therapeutic strategy for selectively targeting ARID1A-deficient HCC.
ARID1A 是肝细胞癌 (HCC) 中最常见的突变肿瘤抑制基因之一。在这项研究中，我们使用 ARID1A 缺陷型 HCC 细胞进行了 CRISPR-Cas9 合成致死筛选，以确定治疗携带 ARID1A 缺陷的 HCC 患者的方法。该策略表明，这些 ARID1A 缺陷型 HCC 细胞的存活高度依赖于与三羧酸 (TCA) 循环相关的基因。从机制上讲，ARID1A 缺失会抑制关键糖酵解相关基因 PKM 的表达，使细胞葡萄糖代谢从有氧糖酵解转变为依赖 TCA 循环和氧化磷酸化。铜死亡是一种最近定义的铜诱导细胞死亡形式，据报道可直接靶向 TCA 循环。在这里，我们发现 ARID1A 缺陷型 HCC 细胞和异种移植肿瘤对铜处理高度敏感。综上所述，这些结果为 ARID1A 缺失与线粒体呼吸损伤之间的合成致死性提供了证据，表明铜处理构成了一种有前途的治疗策略，可选择性靶向 ARID1A 缺陷型 HCC。
