Zhou Jin, Wang Jinzheng, Chen Chao, Yuan Haoliang, Wen Xiaoan, Sun Hongbin
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009. China.
Med Chem. 2018;14(1):3-18. doi: 10.2174/1573406413666171020115539.
USP7 (ubiquitin specific protease 7, also known as HAUSP) is one of the deubiquitinating enzymes (DUB) that reverses ubiquitination and spares substrate proteins from degradation.
After a brief introduction of ubiquitin-proteasome system (UPS) and human DUB, this review focuses on the structural and functional complexity of USP7 in tumor development and progression. Afterwards, physiological regulatory mechanisms and manipulation strategies for USP7 are elaborated. Finally, we discuss the advances and difficulties of USP7 as a novel therapeutic target for cancer.
It is mostly concerned that USP7 regulates the dynamics of the p53 and Mdm2 network by deubiquitinating both p53 and its E3 ubiquitin ligase, Mdm2. Recently, USP7 has also been recognized as a regulator of many other tumor associated proteins such as FOXO, PTEN and Claspin, consequently being involved in cell cycle control, DNA damage response, apoptosis and many other cellular processes. Consistently, aberrant USP7 expression and activity have been connected to various types of cancers, which along with lots of validating genetic and functional experiments make this enzyme a compelling target for the treatment of cancer. Currently disclosed inhibitor discovery programs and relevant research have identified several synthetic small molecules, natural compounds, small peptides and one ubiquitin variant that have specific USP7 inhibitory effects and considerable antitumor activities.
Taken together, USP7 is a promising therapeutic target and USP7 inhibitors hold promise as a new approach to cancer therapy.
USP7（泛素特异性蛋白酶7，也称为HAUSP）是一种去泛素化酶（DUB），可逆转泛素化并使底物蛋白免于降解。
在简要介绍泛素-蛋白酶体系统（UPS）和人类DUB之后，本综述重点关注USP7在肿瘤发生和发展中的结构和功能复杂性。随后，阐述了USP7的生理调节机制和调控策略。最后，我们讨论了USP7作为癌症新型治疗靶点的进展和困难。
人们主要关注USP7通过去泛素化p53及其E3泛素连接酶Mdm2来调节p53和Mdm2网络的动态变化。最近，USP7也被认为是许多其他肿瘤相关蛋白（如FOXO、PTEN和Claspin）的调节因子，因此参与细胞周期控制、DNA损伤反应、细胞凋亡和许多其他细胞过程。一致的是，USP7的异常表达和活性与各种类型的癌症有关，这与大量有效的基因和功能实验一起使这种酶成为治疗癌症的一个有吸引力的靶点。目前公开的抑制剂发现计划和相关研究已经确定了几种具有特异性USP7抑制作用和相当抗肿瘤活性的合成小分子、天然化合物、小肽和一种泛素变体。
综上所述，USP7是一个有前景的治疗靶点，USP7抑制剂有望成为癌症治疗的新方法。
