Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death that develops as a consequence of obesity, cirrhosis and chronic hepatitis. However, the pathways along which these changes occur remain incompletely understood. In this study, we show that the deubiquitinase USP30 is abundant in HCCs that arise in mice maintained on high fat diets (HFDs). IKKβ phosphorylated and stabilized USP30, which promoted USP30 to deubiquitinate ATP citrate lyase (ACLY) and fatty acid synthase (FASN). IKKβ also directly phosphorylated ACLY and facilitated the interaction between USP30 and ACLY and the latter's deubiquitination. In HCCs arising in DEN/CCl4 -treated mice, USP30 deletion attenuated lipogenesis, inflammation and tumorigenesis irrespective of diet. The combination of ACLY inhibitor and PD-L1 antibody largely suppressed chemical-induced hepatocarcinogenesis. The IKKβ-USP30-ACLY axis was also found to be upregulated in human HCCs. Conclusion: This study identifies a new IKKβ-USP30-ACLY axis that plays an essential and wide-spread role in tumor metabolism and may be a potential therapeutic target in HCC.

中文翻译：

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IKKβ-USP30-ACLY 轴控制脂肪生成和肿瘤发生

肝细胞癌 (HCC) 是导致肥胖、肝硬化和慢性肝炎导致的癌症相关死亡的主要原因。然而，这些变化发生的途径仍然不完全清楚。在这项研究中，我们表明去泛素化酶 USP30 在高脂肪饮食 (HFD) 维持的小鼠中出现的 HCC 中含量丰富。IKKβ 磷酸化并稳定 USP30，促进 USP30 去泛素化 ATP 柠檬酸裂解酶 (ACLY) 和脂肪酸合酶 (FASN)。IKKβ 还直接磷酸化 ACLY，促进 USP30 和 ACLY 之间的相互作用以及后者的去泛素化。在 DEN/CCl4 治疗的小鼠中出现的 HCC 中，USP30 缺失减弱了脂肪生成、炎症和肿瘤发生，而与饮食无关。ACLY 抑制剂和 PD-L1 抗体的组合在很大程度上抑制了化学诱导的肝癌发生。还发现 IKKβ-USP30-ACLY 轴在人类 HCC 中上调。结论：本研究确定了一个新的 IKKβ-USP30-ACLY 轴，该轴在肿瘤代谢中发挥重要且广泛的作​​用，可能是 HCC 的潜在治疗靶点。