Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, 112, Taiwan.
Department of Nephrology, Chang-Gung Memorial Hospital, Keelung, 204, Taiwan.
Sci Rep. 2018 Feb 15;8(1):3102. doi: 10.1038/s41598-018-21476-w.
Ubiquitin-specific protease 2 (USP2) belongs to the family of deubiquitinases that can rescue protein targets from proteasomal degradation by reversing their ubiquitination. In various cancers, including prostate cancer and ovarian carcinoma, upregulation of USP2 leads to an increase in the levels of deubiquitinated substrates such as fatty acid synthase, MDM2, cyclin D1 and Aurora-A. USP2 thus plays a critical role in tumor cells' survival and therefore represents a therapeutic target. Here a leukemia drug, 6-thioguanine, was found to be a potent inhibitor of USP2. Enzyme-kinetic and X-ray crystallographic data suggest that 6-thioguanine displays a noncompetitive and slow-binding inhibitory mechanism against USP2. Our study provides a clear rationale for the clinical evaluation of 6-thioguanine for USP2-upregulated cancers.
泛素特异性蛋白酶 2（USP2）属于去泛素化酶家族，能够通过逆转靶蛋白的泛素化来阻止其被蛋白酶体降解。在包括前列腺癌和卵巢癌在内的多种癌症中，USP2 的上调导致去泛素化底物（如脂肪酸合酶、MDM2、细胞周期蛋白 D1 和 Aurora-A）水平增加。因此，USP2 在肿瘤细胞的存活中起着关键作用，因此成为一个治疗靶点。在这里，一种白血病药物 6-硫鸟嘌呤被发现是 USP2 的有效抑制剂。酶动力学和 X 射线晶体学数据表明，6-硫鸟嘌呤对 USP2 表现出非竞争性和缓慢结合的抑制机制。我们的研究为临床评估 6-硫鸟嘌呤治疗 USP2 上调的癌症提供了明确的依据。
