Deubiquitinating enzyme JOSD2 promotes hepatocellular carcinoma progression through interacting with and inhibiting CTNNB1 degradation
Deubiquitinating enzyme JOSD2 promotes hepatocellular carcinoma progression through interacting with and inhibiting CTNNB1 degradation
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DOI：
10.1002/cbin.11812
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发表时间：
2022-05-14
影响因子：
3.9
通讯作者：
Zeng, Jinhua
中科院分区：
文献类型：
--
作者：
Huang, Yao;Zeng, Jianxing;Zeng, Jinhua
尽管已经鉴定了多种分子靶点，但肝细胞癌（HCC）仍然是死亡的主要原因之一。由于去泛素化酶Josephin domain containing 2（JOSD 2）在肿瘤中的功能尚不清楚，我们研究了其在肝癌发生发展中的作用及其分子机制。在这里，我们指出，JOSD 2表达在HCC患者样本中升高，并与预后不良呈正相关。此外，使用体外模型确定JOSD 2在HCC细胞存活、迁移和侵袭中的促进作用。重要的是，一项机制研究表明，JOSD 2结合并降低了连环蛋白β 1（CTNNB1）的泛素化水平，CTNNB1是Wnt信号传导的关键组分，从而增强了Wnt通路的转导。此外，一系列挽救实验证实了CTNNB1在JOSD 2调节HCC进展中的重要性。我们的研究发现JOSD 2是HCC患者的一种新的预后标志物，并确定CTNNB 1是JOSD 2的关键伴侣和下游靶蛋白，这可能有助于JOSD 2作为HCC治疗的有希望的分子靶点的发展。
Although a variety of molecular targets have been identified, hepatocellular carcinoma (HCC) remains among the leading causes of death. As functions of they deubiquitinating enzyme Josephin domain containing 2 (JOSD2) in cancers are still poorly understood, we investigated its function and molecular mechanism in the regulation of HCC progression. Here, we indicated that JOSD2 expression is elevated in patient samples with HCC and positively associated with poor prognosis. Moreover, the promoting roles of JOSD2 in HCC cell survival, migration, and invasion were determined using in vitro models. Importantly, a mechanistic study revealed that JOSD2 binds to and decreases the ubiquitination level of catenin beta 1 (CTNNB1), a key component of Wnt signaling, thereby augmenting Wnt pathway transduction. Furthermore, a series of rescue experiments confirmed the significance of CTNNB1 in the modulation of HCC progression by JOSD2. Our study uncovered JOSD2 as a novel prognostic marker for patients with HCC and identified CTNNB1 as a pivotal partner and downstream target protein of JOSD2, which may aid in the development of JOSD2 as a promising molecular target for HCC treatment.