Affiliated Longhua People's Hospital, 70570Southern Medical University, Shenzhen, China.
Navy Military Medical University Affiliated 12520Changhai Hospital, Shanghai, China.
Technol Cancer Res Treat. 2022 Jan-Dec;21:15330338221119745. doi: 10.1177/15330338221119745.
TP53 protein is lost or mutated in about half of all types of human cancers and small molecules to regulate mutant p53 repair, or interrupt ubiquitination degradation of p53 induced by E3-ubiquitin ligase Mdm2 have a potential application in clinical application. To inhibit the deubiquitinase activity of 19S proteasome and restore the p53 protein level, in this study, we utilized p53 knockout mice to test the anti-cancer effect of a specific USP14 and UCH37 inhibitor b-AP15. Our results show that UCHL5, USP14 and COPS5 are upregulated in p53-related tumors, and higher expression of these genes results in a shorter overall survival in patients with p53 deficiency. Treatment with b-AP15, a UCHL5 and USP14 deubiquitinating activity inhibitor in 19S regulatory subunit, induces tumor regression and prolong the survival period of tumor-loaded mice through down-regulation of COPS5 and its downstream AP-1 and E2F1, and up-regulation of the cell cycle-related proteins p27 and Cyclin E1. Thus, our results suggested that inhibition of UCHL5 and USP14 deubiquitinating activity in 19S proteasome may contribute an extensive approach to preventing tumor progress due to p53 deficiency.
TP53 蛋白在大约一半的人类癌症类型中丢失或发生突变，小分子可以调节突变型 p53 的修复，或中断 E3-泛素连接酶 Mdm2 诱导的 p53 泛素化降解，具有潜在的临床应用价值。为了抑制 19S 蛋白酶体的去泛素酶活性并恢复 p53 蛋白水平，在这项研究中，我们利用 p53 敲除小鼠来测试特异性 USP14 和 UCH37 抑制剂 b-AP15 的抗癌作用。我们的结果表明，UCHL5、USP14 和 COPS5 在与 p53 相关的肿瘤中上调，这些基因的高表达导致 p53 缺失患者的总生存期更短。用 b-AP15（一种 19S 调节亚基的 UCHL5 和 USP14 去泛素化活性抑制剂）治疗可通过下调 COPS5 及其下游的 AP-1 和 E2F1，以及上调细胞周期相关蛋白 p27 和 Cyclin E1，诱导肿瘤消退并延长荷瘤小鼠的生存期。因此，我们的结果表明，抑制 19S 蛋白酶体中的 UCHL5 和 USP14 去泛素化活性可能为预防由于 p53 缺失导致的肿瘤进展提供一种广泛的方法。
