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Targeting the TCA cycle through cuproptosis confers synthetic lethality on ARID1A-deficient hepatocellular carcinoma
Tao Xing1, Li Li2, Yiran Chen3
1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China.
Abstract:
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.
Insights
Hepatocellular carcinoma (HCC) cells lacking the ARID1A gene depend on the tricarboxylic acid (TCA) cycle for survival. Copper treatment, which targets the TCA cycle, shows promise for treating ARID1A-deficient HCC.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- ARID1A is a frequently mutated tumor suppressor gene in hepatocellular carcinoma (HCC).
- Understanding synthetic lethality in ARID1A-deficient HCC is crucial for developing targeted therapies.
Purpose of the Study:
- To identify therapeutic strategies for hepatocellular carcinoma (HCC) patients with ARID1A deficiency.
- To investigate the metabolic vulnerabilities of ARID1A-deficient HCC cells.
Main Methods:
- Conducted a CRISPR-Cas9 synthetic lethality screen in ARID1A-deficient HCC cells.
- Analyzed cellular glucose metabolism and gene expression changes.
- Assessed sensitivity to copper treatment in vitro and in vivo.
Main Results:
- ARID1A-deficient HCC cells rely on tricarboxylic acid (TCA) cycle genes for survival.
- Loss of ARID1A represses pyruvate kinase M (PKM) expression, shifting metabolism towards TCA cycle dependence.
- ARID1A-deficient HCC cells and tumors exhibit high sensitivity to copper treatment.
Conclusions:
- ARID1A deficiency creates a synthetic lethal vulnerability with impaired mitochondrial respiration.
- Copper treatment is a potential therapeutic strategy for selectively targeting ARID1A-deficient HCC.
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