Lv Xin-You, Duan Ting, Li Jin
Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine Shanghai, China.
Holistic Integrative Pharmacy Institutes, Hangzhou Normal University Hangzhou, Zhejiang, China.
Am J Cancer Res. 2020 Jun 1;10(6):1647-1657. eCollection 2020.
Primary liver cancer ranks the second leading cause of death associated with cancer in the world and therefore a major public health challenge. The mortality rates of liver cancer has been increasing during the past decades with the reality that the alternative therapeutic drugs are not available. Although growing numbers of proteins involved in liver cancer progression have been identified, many of these are not suitable drug targets, which hinders the development of new drugs to cure liver cancer. It is in urgent demand that novel therapeutic approaches should be explored. Deubiquitinases (DUBs), specifically removing ubiquitin chains from the target protein, have showed vital roles for protein homeostasis and quality control by rigidly regulating the balance between ubiquitination and deubiquitination in normal physiology. Recent studies have revealed deregulation or dysfunction of DUBs always associates with cancer and other diseases. Targeting certain DUBs, leading to degradation or loss function of the key oncoproteins, including undruggable ones, seems to provide a potential therapy for cancer patients. In liver cancer, numberous of DUBs are demonstrated to participate in hepatocarcinogenesis, metastasis and so on. Depending on the substrates, some DUBs may suppress liver cancers while others promote. In this review, we primarily summarize the roles of DUBs in liver tumors, and illustrate opportunities for the application of targeting DUBs for cancer therapy.
原发性肝癌是全球与癌症相关的第二大死因，因此是一项重大的公共卫生挑战。在过去几十年中，肝癌的死亡率一直在上升，而现实情况是缺乏替代治疗药物。尽管已发现越来越多与肝癌进展相关的蛋白质，但其中许多并非合适的药物靶点，这阻碍了治疗肝癌新药的研发。迫切需要探索新的治疗方法。去泛素化酶（DUBs）专门从靶蛋白上去除泛素链，通过在正常生理过程中严格调节泛素化和去泛素化之间的平衡，对蛋白质稳态和质量控制发挥着至关重要的作用。最近的研究表明，DUBs的失调或功能障碍总是与癌症和其他疾病相关。靶向某些DUBs，导致关键癌蛋白（包括难以成药的癌蛋白）降解或功能丧失，似乎为癌症患者提供了一种潜在的治疗方法。在肝癌中，大量DUBs被证明参与肝癌发生、转移等过程。根据底物不同，一些DUBs可能抑制肝癌，而另一些则促进肝癌。在本综述中，我们主要总结DUBs在肝肿瘤中的作用，并阐述靶向DUBs用于癌症治疗的应用机会。
