Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, 450052, China.
Commun Biol. 2024 Oct 8;7(1):1279. doi: 10.1038/s42003-024-06999-5.
Ubiquitination is a post-translational modification (PTM), which is critical to maintain cell homeostasis. Ubiquitin-specific protease 24 (USP24) plays roles in various diseases, the mechanisms by which USP24 regulates hepatocellular carcinoma (HCC) remain poorly understood. In this study, USP24 is found to be significantly downregulated in HCC. Knocking down USP24 promotes HCC proliferation and migration, whereas USP24 overexpression inhibits HCC in vitro and in vivo. The endogenous interaction between USP24 and Beclin1 is confirmed. Mechanically, USP24 delays Beclin1 degradation by reducing its K48-linked ubiquitination, the effects of overexpressing USP24 on HCC proliferation can be partially reversed by silencing Beclin1. We find that increased autophagy is accompanied by ferroptosis in USP24 overexpressed HCC cells and USP24 increases the susceptibility of HCC to sorafenib. Collectively, this study highlights the critical role of USP24 in regulating autophagy-dependent ferroptosis by decreasing Beclin1 ubiquitination, suggesting that targeting USP24 may be a strategy for treating HCC.
泛素化是一种翻译后修饰（PTM），对于维持细胞内稳态至关重要。泛素特异性蛋白酶 24（USP24）在各种疾病中发挥作用，但其调节肝细胞癌（HCC）的机制仍知之甚少。本研究发现 USP24 在 HCC 中显著下调。敲低 USP24 促进 HCC 的增殖和迁移，而过表达 USP24 则在体外和体内抑制 HCC。内源性 USP24 与 Beclin1 之间的相互作用得到证实。在机制上，USP24 通过减少其 K48 连接的泛素化来延迟 Beclin1 的降解，而过表达 USP24 对 HCC 增殖的影响可以通过沉默 Beclin1 部分逆转。我们发现，在 USP24 过表达的 HCC 细胞中，自噬增加伴随着铁死亡，并且 USP24 增加了 HCC 对索拉非尼的敏感性。综上所述，本研究强调了 USP24 通过减少 Beclin1 泛素化来调节自噬依赖性铁死亡的关键作用，表明靶向 USP24 可能是治疗 HCC 的一种策略。
