Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China; Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, Gansu, China; Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu, China.
Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China.
Exp Cell Res. 2022 Oct 1;419(1):113293. doi: 10.1016/j.yexcr.2022.113293. Epub 2022 Jul 19.
Ubiquitin binding enzyme E2S (UBE2S) is a member of ubiquitin binding enzyme family involved in a variety of biological functions, including cell cycle regulation, apoptosis, and regulation of the ubiquitination of proteins, which are closely correlated with the development of various tumors. However, its role in gastric cancer (GC) remains unknown. In this study, we found that UBE2S was upregulated in GC tissues and cells. Further, its high expression positively correlated with the tumor stage and indicated a poor prognosis. Knockout of UBE2S by CRISPR/Cas9-mediated strategy suppressed the growth of GC in vitro and in vivo. Moreover, RNA-Seq-based transcriptome analysis and tandem mass tag (TMT)-based quantitative proteomics analysis was performed for exploring the underlying mechanism. The multi-omics and verification results showed that UBE2S knockout-induced apoptosis and proliferation inhibition of GC cells was related to upregulation of FAS and the activation of the FAS-mediated apoptotic pathway. Moreover, a negative correlation between UBE2S and FAS expression was observed in GC tissue samples. Finally, the ubiquitination assay confirmed that knockout of UBE2S might activate endogenous FAS by inhibiting ubiquitination and degradation of p53 in GC cells. Collectively, UBE2S is expected to be a novel prognostic biomarker and potential therapeutic target for GC.
泛素结合酶 E2S（UBE2S）是泛素结合酶家族的成员，参与多种生物学功能，包括细胞周期调节、细胞凋亡和蛋白质的泛素化调节，这些过程与各种肿瘤的发生发展密切相关。然而，其在胃癌（GC）中的作用尚不清楚。本研究发现 UBE2S 在 GC 组织和细胞中呈高表达。进一步研究发现，UBE2S 的高表达与肿瘤分期呈正相关，提示预后不良。通过 CRISPR/Cas9 介导的策略敲除 UBE2S 可抑制 GC 在体外和体内的生长。此外，还进行了基于 RNA-Seq 的转录组分析和基于串联质量标签（TMT）的定量蛋白质组学分析，以探索潜在的机制。多组学和验证结果表明，UBE2S 敲除诱导的 GC 细胞凋亡和增殖抑制与 FAS 的上调和 FAS 介导的凋亡途径的激活有关。此外，在 GC 组织样本中观察到 UBE2S 与 FAS 表达之间存在负相关。最后，泛素化实验证实，UBE2S 的敲除可能通过抑制 GC 细胞中 p53 的泛素化和降解来激活内源性 FAS。总之，UBE2S 有望成为 GC 的一种新的预后生物标志物和潜在的治疗靶点。
