Strictly regulated protein degradation by ubiquitin-proteasome system (UPS) is essential for various cellular processes whose dysregulation is linked to serious diseases including cancer. Skp2, a well characterized component of Skp2-SCF E3 ligase complex, is able to conjugate both K48-linked ubiquitin chains and K63-linked ubiquitin chains on its diverse substrates, inducing proteasome mediated proteolysis or modulating the function of tagged substrates respectively. Overexpression of Skp2 is observed in various human cancers associated with poor survival and adverse therapeutic outcomes, which in turn suggests that Skp2 engages in tumorigenic activity. To that end, the oncogenic properties of Skp2 are demonstrated by various genetic mouse models, highlighting the potential of Skp2 as a target for tackling cancer. In this article, we will describe the downstream substrates of Skp2 as well as upstream regulators for Skp2-SCF complex activity. We will further summarize the comprehensive oncogenic functions of Skp2 while describing diverse strategies and therapeutic platforms currently available for developing Skp2 inhibitors.

泛素-蛋白酶体系统 (UPS) 严格调节蛋白质降解对于各种细胞过程至关重要，这些过程的失调与包括癌症在内的严重疾病有关。Skp2 是 Skp2-SCF E3 连接酶复合物的一个很好表征的成分，能够在其不同的底物上结合 K48 连接的泛素链和 K63 连接的泛素链，分别诱导蛋白酶体介导的蛋白水解或调节标记底物的功能。在与生存率低和不良治疗结果相关的各种人类癌症中观察到 Skp2 的过度表达，这反过来表明 Skp2 参与了致瘤活动。为此，各种遗传小鼠模型证明了 Skp2 的致癌特性，突出了 Skp2 作为治疗癌症靶点的潜力。在本文中，我们将描述 Skp2 的下游底物以及 Skp2-SCF 复合物活性的上游调节剂。我们将进一步总结 Skp2 的综合致癌功能，同时描述目前可用于开发 Skp2 抑制剂的各种策略和治疗平台。