UEV1A encodes a ubiquitin-E2 variant closely associated with tumorigenesis and metastasis, but its underlying mechanism in promoting metastasis remains to be investigated. In this study, we experimentally manipulated UEV1A and CT45A gene expression and monitored their effects on cancer-related gene expression, cell migration and the signal transduction cascade. It was found that UEV1A overexpression induces CT45A family gene expression in breast cancer cells. Indeed, ectopic expression of UEV1A was sufficient to induce CT45A and its downstream genes involved in tumorigenesis, epithelial-mesenchymal transition (EMT), stemness and metastasis, and to promote cell migration and EMT signaling. Consistently, depletion of CT45A abolished the above effects, indicating that CT45A is a critical downstream effector of Uev1A. The Uev1A-induced cell migration and EMT signaling was dependent on AKT but independent of NF-κB, indicating that CT45A acts downstream of the AKT pathway. Based on previous reports and observations in this study, we propose that the Ubc13-Uev1A complex activates AKT through K63-linked polyubiquitination, which leads to enhanced CT45A expression, stimulated cell migration and EMT signaling in breast cells. Since similar effects were also observed in a colorectal cancer cell line, the Ubc13/Uev1A-AKT-CT45A axis may also promote tumorigenesis and metastasis in other tissues.

中文翻译：

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Uev1A通过AKT通路上调CT45A表达促进乳腺癌细胞迁移

UEV1A 编码与肿瘤发生和转移密切相关的泛素-E2 变体，但其促进转移的潜在机制仍有待研究。在这项研究中，我们通过实验操纵 UEV1A 和 CT45A 基因表达并监测它们对癌症相关基因表达、细胞迁移和信号转导级联的影响。发现UEV1A过表达诱导乳腺癌细胞中CT45A家族基因表达。事实上，UEV1A 的异位表达足以诱导 CT45A 及其下游基因参与肿瘤发生、上皮间质转化 (EMT)、干细胞和转移，并促进细胞迁移和 EMT 信号传导。一致地，CT45A 的消耗消除了上述效应，表明 CT45A 是 Uev1A 的关键下游效应器。Uev1A 诱导的细胞迁移和 EMT 信号依赖于 AKT 但不依赖于 NF-κB，表明 CT45A 作用于 AKT 通路的下游。根据之前的报告和本研究中的观察，我们提出 Ubc13-Uev1A 复合物通过 K63 连接的多泛素化激活 AKT，从而导致 CT45A 表达增强，刺激乳腺细胞中的细胞迁移和 EMT 信号传导。由于在结直肠癌细胞系中也观察到类似的作用，Ubc13/Uev1A-AKT-CT45A 轴也可能促进其他组织的肿瘤发生和转移。这导致 CT45A 表达增强，刺激乳腺细胞中的细胞迁移和 EMT 信号传导。由于在结直肠癌细胞系中也观察到类似的作用，Ubc13/Uev1A-AKT-CT45A 轴也可能促进其他组织的肿瘤发生和转移。这导致 CT45A 表达增强，刺激乳腺细胞中的细胞迁移和 EMT 信号传导。由于在结直肠癌细胞系中也观察到类似的作用，Ubc13/Uev1A-AKT-CT45A 轴也可能促进其他组织的肿瘤发生和转移。