RING-in-between-RING (RBR) E3 ligases are one class of E3 ligases that is characterized by the unique RING-HECT hybrid mechanism to function with E2s to transfer ubiquitin to target proteins for degradation. Emerging evidence has demonstrated that RBR E3 ligases play essential roles in neurodegenerative diseases, infection, inflammation and cancer. Accumulated evidence has revealed that RBR E3 ligases exert their biological functions in various types of cancers by modulating the degradation of tumor promoters or suppressors. Hence, we summarize the differential functions of RBR E3 ligases in a variety of human cancers. In general, ARIH1, RNF14, RNF31, RNF144B, RNF216, and RBCK1 exhibit primarily oncogenic roles, whereas ARIH2, PARC and PARK2 mainly have tumor suppressive functions. Moreover, the underlying mechanisms by which different RBR E3 ligases are involved in tumorigenesis and progression are also described. We discuss the further investigation is required to comprehensively understand the critical role of RBR E3 ligases in carcinogenesis. We hope our review can stimulate the researchers to deeper explore the mechanism of RBR E3 ligases-mediated carcinogenesis and to develop useful inhibitors of these oncogenic E3 ligases for cancer therapy.

RING-in-between-RING (RBR) E3 连接酶是一类 E3 连接酶，其特征在于独特的 RING-HECT 混合机制与 E2 一起将泛素转移到目标蛋白进行降解。新出现的证据表明，RBR E3 连接酶在神经退行性疾病、感染、炎症和癌症中发挥着重要作用。越来越多的证据表明，RBR E3 连接酶通过调节肿瘤启动子或抑制子的降解在各种类型的癌症中发挥其生物学功能。因此，我们总结了 RBR E3 连接酶在各种人类癌症中的不同功能。一般来说，ARIH1、RNF14、RNF31、RNF144B、RNF216和RBCK1主要表现出致癌作用，而ARIH2、PARC和PARK2主要具有肿瘤抑制功能。而且，还描述了不同 RBR E3 连接酶参与肿瘤发生和进展的潜在机制。我们讨论需要进一步调查以全面了解 RBR E3 连接酶在致癌作用中的关键作用。我们希望我们的评论能够激发研究人员更深入地探索 RBR E3 连接酶介导的致癌机制，并开发这些致癌 E3 连接酶用于癌症治疗的有用抑制剂。