Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy.
Int J Biol Sci. 2024 Sep 23;20(13):5208-5222. doi: 10.7150/ijbs.100355. eCollection 2024.
Ovarian cancer is a lethal disease due to late diagnosis and occurrence of drug resistance that limits the efficacy of platinum-based therapy. Drug resistance mechanisms include both tumor intrinsic and tumor microenvironment-related factors. A role for deubiquitinases (DUBs) is starting to emerge in ovarian cancer. DUBs are a large family of enzymes that remove ubiquitin from target proteins and participate in processes affecting drug resistance such as DNA damage repair and apoptosis. Besides, DUBs modulate the functions of T cell populations favoring an immune suppressed microenvironment. Three DUBs are proteasome-associated, whereas the large majority are not. Among the former DUBs, USP14 has been proposed to modulate transcription factors such as Bcl6 and BACH1. In addition, RPN11/PSMD14 interferes with various processes including epithelial mesenchymal transition, also favored by non-proteasomal DUBs such as USP1 by acting on Snail. Besides, USP8 by stabilizing HER family receptors can confer drug resistance. Overall, DUBs appear to be druggable, with several inhibitors under development. Based on DUBs biological role, DUBs targeting appears promising in view of combination strategies involving different therapeutic approaches. Here, we summarize the relevance of DUBs in ovarian carcinoma and provide insights into future challenges for the treatment of this disease.
卵巢癌是一种致命的疾病，其诊断较晚，且容易发生耐药性，从而限制了基于铂类的治疗效果。耐药机制包括肿瘤内在和肿瘤微环境相关因素。去泛素化酶（DUBs）在卵巢癌中的作用开始显现。DUBs 是一大类酶，可从靶蛋白上去除泛素，并参与影响耐药性的过程，如 DNA 损伤修复和细胞凋亡。此外，DUBs 调节 T 细胞群的功能，有利于免疫抑制的微环境。三种 DUBs 与蛋白酶体有关，而绝大多数则没有。在前者中，USP14 被提议调节转录因子，如 Bcl6 和 BACH1。此外，RPN11/PSMD14 干扰多种过程，包括上皮间质转化，非蛋白酶体 DUBs 如 USP1 也通过作用于 Snail 促进其发生。此外，USP8 通过稳定 HER 家族受体可以赋予耐药性。总的来说，DUBs 似乎是可用药的，有几种抑制剂正在开发中。基于 DUBs 的生物学作用，针对 DUBs 的靶向治疗似乎很有希望，因为它涉及不同治疗方法的联合策略。在这里，我们总结了 DUBs 在卵巢癌中的相关性，并为该疾病的治疗提供了未来的挑战。
