Abstract Regulation of target proteins by the ubiquitin-proteasome system (UPS) is common in a wide range of cellular events, including transcriptional regulation, cell cycle progression, differentiation, and tumorigenesis. Ubiquitin-specific protease 7 (USP7) has been implicated in tumor development and metastasis in various malignancies through the regulation of target protein stability. In this study, we found that the enhancer of zeste homolog 2 (EZH2), which catalyzes the methylation at lysine 27 of histone H3, is a target of USP7 and is stabilized by USP7-mediated deubiquitination. In prostate cancer cells, the transcriptional repression function of EZH2 was inhibited by USP7-knockdown. Furthermore, ectopic introduction of EZH2 restored the cell migration, invasion, and sphere-forming potential of prostate cancer cells, which had been decreased by USP7-knockdown. Moreover, combined treatment with the USP7-specific inhibitor P5091 and EZH2 inhibitors, such as GSK126, EPZ6438, and DZNep, induced synergistic inhibitory effects on cell migration, invasion, and sphere-forming potential in prostate cancer cells. Collectively, our findings revealed that the promotion of the malignancy-associated characteristics of prostate cancer cells by USP7 was in part due to EZH2 stabilization. Thus, we suggest that simultaneous treatment with a USP7 inhibitor and an EZH2 inhibitor could be a rational strategy for treating EZH2-dependent cancers.

中文翻译：

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USP7 去泛素化并稳定前列腺癌细胞中的 EZH2

摘要 泛素-蛋白酶体系统 (UPS) 对靶蛋白的调控在广泛的细胞事件中很常见，包括转录调控、细胞周期进程、分化和肿瘤发生。泛素特异性蛋白酶 7 (USP7) 已通过调节靶蛋白稳定性参与各种恶性肿瘤的肿瘤发展和转移。在本研究中，我们发现催化组蛋白 H3 赖氨酸 27 甲基化的 zeste 同源物 2 (EZH2) 的增强子是 USP7 的靶标，并通过 USP7 介导的去泛素化稳定。在前列腺癌细胞中，EZH2 的转录抑制功能被 USP7 敲低抑制。此外，异位引入 EZH2 恢复了前列腺癌细胞的细胞迁移、侵袭和球形成潜力，已因 USP7 击倒而减少。此外，与 USP7 特异性抑制剂 P5091 和 EZH2 抑制剂（如 GSK126、EPZ6438 和 DZNep）联合治疗，对前列腺癌细胞中的细胞迁移、侵袭和球形成潜力产生协同抑制作用。总的来说，我们的研究结果表明，USP7 促进前列腺癌细胞的恶性肿瘤相关特征部分是由于 EZH2 稳定。因此，我们建议同时使用 USP7 抑制剂和 EZH2 抑制剂治疗可能是治疗 EZH2 依赖性癌症的合理策略。和前列腺癌细胞中的球体形成潜力。总的来说，我们的研究结果表明，USP7 促进前列腺癌细胞的恶性肿瘤相关特征部分是由于 EZH2 稳定。因此，我们建议同时使用 USP7 抑制剂和 EZH2 抑制剂治疗可能是治疗 EZH2 依赖性癌症的合理策略。和前列腺癌细胞中的球体形成潜力。总的来说，我们的研究结果表明，USP7 促进前列腺癌细胞的恶性肿瘤相关特征部分是由于 EZH2 稳定。因此，我们建议同时使用 USP7 抑制剂和 EZH2 抑制剂治疗可能是治疗 EZH2 依赖性癌症的合理策略。