Department of Hepatobiliary Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
Department of Hepatic Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.
Cell Biol Int. 2022 Jul;46(7):1089-1097. doi: 10.1002/cbin.11812. Epub 2022 May 14.
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.
尽管已经确定了多种分子靶点，但肝细胞癌（HCC）仍然是主要死亡原因之一。由于去泛素化酶 Josephin 结构域包含 2 （JOSD2）在癌症中的功能仍知之甚少，我们研究了其在调节 HCC 进展中的功能和分子机制。在这里，我们表明 JOSD2 在 HCC 患者样本中的表达升高，并与预后不良呈正相关。此外，使用体外模型确定了 JOSD2 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，JOSD2 与 Wnt 信号通路的关键组成部分连环蛋白 beta 1（CTNNB1）结合并降低其泛素化水平，从而增强 Wnt 途径转导。此外，一系列挽救实验证实了 CTNNB1 在 JOSD2 调节 HCC 进展中的重要性。我们的研究揭示了 JOSD2 作为 HCC 患者的新型预后标志物，并确定 CTNNB1 是 JOSD2 的关键伙伴和下游靶蛋白，这可能有助于将 JOSD2 作为 HCC 治疗的有前途的分子靶标进行开发。
