USP11 is a member of the ubiquitin-specific protease family and plays a crucial role in tumor progression in various cancers. However, the precise mechanism by which USP11 promotes EMT and metastasis in hepatocellular carcinoma (HCC) is not fully understood. In this study, we demonstrated that the USP11 expression was dramatically upregulated in HCC tissues and cell lines. Increased USP11 expression was closely associated with tumor number, vascular invasion, and poor prognosis. Functional experiments demonstrated that USP11 markedly promoted metastasis and EMT in HCC via induction of the transcription factor Snail. Mechanistically, USP11 interacted with and deubiquitinated eEF1A1 on Lys439, thereby inhibiting its ubiquitin-mediated degradation. Subsequently, the elevated expression of eEF1A1 resulted in its binding to SP1, which in turn drove the binding of SP1 to its target HGF gene promoter to increase its transcription. This led to an enhanced expression of HGF and the activation of the downstream PI3K/AKT signaling pathway. We demonstrated that USP11 promotes EMT and metastasis in HCC via eEF1A1/SP1/HGF dependent-EMT. Our findings suggest that the USP11/ eEF1A1/SP1/HGF axis contributes to metastasis in HCC, and therefore, could be considered as a potential therapeutic target for the treatment of HCC.

USP11 是泛素特异性蛋白酶家族的成员，在各种癌症的肿瘤进展中发挥着至关重要的作用。然而，USP11促进肝细胞癌（HCC）EMT和转移的确切机制尚不完全清楚。在这项研究中，我们证明 USP11 表达在 HCC 组织和细胞系中显着上调。 USP11表达增加与肿瘤数量、血管侵犯和不良预后密切相关。功能实验表明，USP11 通过诱导转录因子 Snail 显着促进 HCC 的转移和 EMT。从机制上讲，USP11 与 Lys439 上的 eEF1A1 相互作用并使 eEF1A1 去泛素化，从而抑制其泛素介导的降解。随后，eEF1A1的表达升高导致其与SP1结合，进而驱动SP1与其目标HGF基因启动子结合以增加其转录。这导致 HGF 表达增强并激活下游 PI3K/AKT 信号通路。我们证明 USP11 通过 eEF1A1/SP1/HGF 依赖性 EMT 促进 HCC 中的 EMT 和转移。我们的研究结果表明，USP11/eEF1A1/SP1/HGF 轴有助于 HCC 的转移，因此可以被视为治疗 HCC 的潜在治疗靶点。