PDF(Pubmed)
Abstract：
Ubiquitination, a prevalent and highly dynamic reversible post-translational modification, is tightly regulated by the deubiquitinating enzymes (DUBs) superfamily. Among them, OTU Domain-Containing Ubiquitin Aldehyde-Binding Protein 1 (OTUB1) stands out as a critical member of the OTU deubiquitinating family, playing a pivotal role as a tumor regulator across various cancers. However, its specific involvement in BLCA (BLCA) and its clinical significance have remained ambiguous. This study aimed to elucidate the biofunctions of OTUB1 in BLCA and its implications for clinical prognosis. Our investigation revealed heightened OTUB1 expression in BLCA, correlating with unfavorable clinical outcomes. Through in vivo and in vitro experiments, we demonstrated that increased OTUB1 levels promote BLCA tumorigenesis and progression, along with conferring resistance to cisplatin treatment. Notably, we established a comprehensive network involving OTUB1, β-catenin, necroptosis, and BLCA, delineating their regulatory interplay. Mechanistically, we uncovered that OTUB1 exerts its influence by deubiquitinating and stabilizing β-catenin, leading to its nuclear translocation. Subsequently, nuclear β-catenin enhances the transcriptional activity of c-myc and cyclin D1 while suppressing the expression of RIPK3 and MLKL, thereby fostering BLCA progression and cisplatin resistance. Importantly, our clinical data suggest that the OTUB1/β-catenin/RIPK3/MLKL axis holds promise as a potential biomarker for BLCA.
摘要：
泛素化,一种普遍且高度动态的可逆翻译后修饰，受到去泛素化酶（DUBs）超家族的严格调控。其中,含OTU结构域的泛素醛结合蛋白1（OTUB1）是OTU去泛素家族的关键成员，在各种癌症中作为肿瘤调节剂发挥关键作用。然而,其在BLCA（BLCA）中的具体参与及其临床意义仍然不明确。本研究旨在阐明OTUB1在BLCA中的生物学功能及其对临床预后的影响。我们的调查显示，BLCA中OTUB1的表达增加，与不利的临床结果相关。通过体内和体外实验，我们证明，增加OTUB1水平促进BLCA肿瘤发生和进展，同时赋予顺铂治疗耐药性。值得注意的是,我们建立了一个涉及OTUB1、β-catenin、坏死,BLCA,描述它们之间的监管相互作用。机械上,我们发现OTUB1通过去泛素化和稳定β-catenin发挥其影响，导致其核易位。随后，核β-catenin增强c-myc和cyclinD1的转录活性，同时抑制RIPK3和MLKL的表达，从而促进BLCA进展和顺铂耐药。重要的是,我们的临床数据提示OTUB1/β-catenin/RIPK3/MLKL轴有望成为BLCA的潜在生物标志物.
