Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Leioa, Spain.
Mol Cancer. 2013 Aug 10;12:91. doi: 10.1186/1476-4598-12-91.
Reversible protein ubiquitination is emerging as a key process for maintaining cell homeostasis, and the enzymes that participate in this process, in particular E3 ubiquitin ligases and deubiquitinases (DUBs), are increasingly being regarded as candidates for drug discovery. Human DUBs are a group of approximately 100 proteins, whose cellular functions and regulatory mechanisms remain, with some exceptions, poorly characterized. One of the best-characterized human DUBs is ubiquitin-specific protease 1 (USP1), which plays an important role in the cellular response to DNA damage. USP1 levels, localization and activity are modulated through several mechanisms, including protein-protein interactions, autocleavage/degradation and phosphorylation, ensuring that USP1 function is carried out in a properly regulated spatio-temporal manner. Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy. This view has gained recent support with the finding that USP1 inhibition may contribute to revert cisplatin resistance in an in vitro model of non-small cell lung cancer (NSCLC). Here, we describe the current knowledge on the cellular functions and regulatory mechanisms of USP1. We also summarize USP1 alterations found in cancer, combining data from the literature and public databases with our own data. Finally, we discuss the emerging potential of USP1 as a target, integrating published data with our novel findings on the effects of the USP1 inhibitor pimozide in combination with cisplatin in NSCLC cells.
蛋白质可逆泛素化是维持细胞内稳态的关键过程，参与这一过程的酶，特别是 E3 泛素连接酶和去泛素化酶（DUBs），越来越被视为药物发现的候选物。人类 DUBs 是一组约 100 种蛋白质，其细胞功能和调节机制除了一些例外，仍然知之甚少。其中研究得最为透彻的人类 DUBs 是泛素特异性蛋白酶 1（USP1），它在细胞对 DNA 损伤的反应中起着重要作用。USP1 的水平、定位和活性通过几种机制进行调节，包括蛋白-蛋白相互作用、自身切割/降解和磷酸化，以确保 USP1 功能以适当调节的时空方式进行。重要的是，USP1 的表达在某些类型的人类癌症中失调，这表明 USP1 可能是癌症治疗的一个有效靶点。最近的研究结果支持了这一观点，即 USP1 抑制可能有助于逆转体外非小细胞肺癌（NSCLC）模型中的顺铂耐药性。在这里，我们描述了 USP1 的细胞功能和调节机制的现有知识。我们还总结了癌症中发现的 USP1 改变，结合文献和公共数据库中的数据以及我们自己的数据。最后，我们讨论了 USP1 作为一个靶点的新出现的潜力，将已发表的数据与我们关于 USP1 抑制剂匹莫齐德与顺铂联合应用于 NSCLC 细胞的影响的新发现结合起来。
