USP11 potentiates HGF/AKT signaling and drives metastasis in hepatocellular carcinoma
USP11 potentiates HGF/AKT signaling and drives metastasis in hepatocellular carcinoma
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DOI：
10.1038/s41388-023-02847-8
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发表时间：
2023-11-16
期刊：
影响因子：
8
通讯作者：
Chen，Xiaoping
中科院分区：
文献类型：
--
作者：
Chen，Jin;Ning，Deng;Chen，Xiaoping
USP 11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起着至关重要的作用。然而，USP 11促进肝细胞癌（HCC）EMT和转移的确切机制尚未完全了解。在这项研究中，我们证明了USP 11在HCC组织和细胞系中的表达显著上调。USP 11表达增加与肿瘤数量、血管浸润和预后不良密切相关。功能实验表明，USP 11通过诱导转录因子Snail显著促进HCC的转移和EMT。在机制上，USP 11与Lys 439上的eEF 1A 1相互作用并使其去泛素化，从而抑制其泛素介导的降解。随后，eEF 1A 1的表达升高导致其与SP1结合，这反过来又驱动SP1与其靶HGF基因启动子结合以增加其转录。这导致HGF的表达增强和下游PI 3 K/AKT信号通路的激活。我们证明USP 11通过eEF 1A 1/SP1/HGF依赖性EMT促进HCC中的EMT和转移。我们的研究结果表明，USP 11/eEF 1A 1/SP1/HGF轴有助于肝癌的转移，因此，可以被认为是一个潜在的治疗肝癌的治疗靶点。
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.