Qiu Y U, Liu Ruihan, Huang Shanshan, Cai Qiaoting, Xie Y I, He Zhiting, Tan Weige, Xie Xinhua
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510030, China.
Department of Breast Surgery, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510030, China.
Oncol Res. 2025 Apr 18;33(5):1135-1147. doi: 10.32604/or.2025.062767. eCollection 2025.
Deubiquitinase OTUB2 plays a critical role in the progression of various tumors. However, its specific role in triple-negative breast cancer (TNBC) remains unclear. This study aims to elucidate the biological function of OTUB2 in TNBC and uncover the underlying mechanisms.
First, we found that the expression of was upregulated in TNBC by bioinformatics analysis, we then validated its expression in TNBC tissues and cells using immunohistochemistry (IHC) and qPCR and plotted the survival curves by Kaplan-Meier method. Gene set enrichment analysis (GSEA) suggested that OTUB2 may be involved in tumor proliferation and metastasis. Further functional assays, including Cell Counting Kit-8 (CCK-8), colony formation, Transwell, and wound healing assays, were performed to assess the effects of OTUB2 overexpression and knockdown on TNBC cell proliferation and migration. Additionally, UbiBrowser 2.0 was used to identify OTUB2 substrate proteins and western blotting was conducted to clarify the molecular mechanisms involved.
Our results demonstrated that OTUB2 expression was elevated in TNBC and associated with poor prognosis. Overexpression of OTUB2 enhanced the proliferation and migration of TNBC cells, while its knockdown inhibited these processes. Moreover, OTUB2 stabilized tumor necrosis factor receptor-associated factor 6 (TRAF6) by deubiquitinating it, leading to activation of the protein kinase B (AKT) pathway.
OTUB2 exerts its promoting effects on the progression of TNBC by activating the TRAF6/AKT pathway.
去泛素化酶OTUB2在多种肿瘤进展中起关键作用。然而，其在三阴性乳腺癌（TNBC）中的具体作用仍不清楚。本研究旨在阐明OTUB2在TNBC中的生物学功能并揭示其潜在机制。
首先，通过生物信息学分析发现OTUB2在TNBC中表达上调，随后我们使用免疫组织化学（IHC）和qPCR验证其在TNBC组织和细胞中的表达，并采用Kaplan-Meier法绘制生存曲线。基因集富集分析（GSEA）表明OTUB2可能参与肿瘤增殖和转移。进行了包括细胞计数试剂盒-8（CCK-8）、集落形成、Transwell和伤口愈合试验在内的进一步功能试验，以评估OTUB2过表达和敲低对TNBC细胞增殖和迁移的影响。此外，使用UbiBrowser 2.0鉴定OTUB2底物蛋白，并进行蛋白质印迹以阐明其中涉及的分子机制。
我们的结果表明，OTUB2在TNBC中表达升高且与预后不良相关。OTUB2的过表达增强了TNBC细胞的增殖和迁移，而其敲低则抑制了这些过程。此外，OTUB2通过去泛素化稳定肿瘤坏死因子受体相关因子6（TRAF6），导致蛋白激酶B（AKT）通路激活。
OTUB2通过激活TRAF6/AKT通路对TNBC的进展发挥促进作用。
