Abstract：
Hepatocellular carcinoma (HCC) is the predominant form of liver cancer, characterized by high morbidity and mortality rates, as well as unfavorable treatment outcomes. Tripartite motif-containing protein 47 (TRIM47) has been implicated in various diseases including tumor progression with the activity of E3 ubiquitin ligase. However, the precise regulatory mechanisms underlying the involvement of TRIM47 in HCC remain largely unexplored. Here, we provide evidence that TRIM47 exhibits heightened expression in tumor tissues, and its expression is in intimate association with clinical staging and patient prognosis. TRIM47 promotes HCC proliferation, migration, and invasion as an oncogene by in vitro gain- and loss-of-function experiments. TRIM47 knockdown results in HCC ferroptosis induction, primarily through CDO1 involvement to regulate GSH synthesis. Subsequent experiments confirm the interaction between TRIM47 and CDO1 dependent on B30.2 domain, wherein TRIM47 facilitates K48-linked ubiquitination, leading to a decrease in CDO1 protein abundance in HCC. Furthermore, CDO1 is able to counteract the promotional effect of TRIM47 on HCC biological functions. Overall, our research provides novel insight into the mechanism of TRIM47 in CDO1-mediated ferroptosis in HCC cells, highlighting its value as a potential target candidate for HCC therapeutic approaches.
摘要：
肝细胞癌（HCC）是肝癌的主要形式，其特点是发病率和死亡率高，以及不利的治疗结果。含有三方基序的蛋白47（TRIM47）与各种疾病有关，包括具有E3泛素连接酶活性的肿瘤进展。然而,TRIM47参与HCC的精确调控机制在很大程度上仍未被探索.这里,我们提供的证据表明，TRIM47在肿瘤组织中表达增加，其表达与临床分期和患者预后密切相关。TRIM47促进HCC增殖，迁移,通过体外功能增益和功能丧失实验，将侵袭作为癌基因。TRIM47敲低导致HCC铁凋亡诱导，主要通过CDO1参与调节GSH合成。随后的实验证实了TRIM47和CDO1之间的相互作用依赖于B30.2结构域，其中TRIM47促进K48连接的泛素化，导致肝癌中CDO1蛋白丰度降低。此外，CDO1能够抵消TRIM47对HCC生物学功能的促进作用。总的来说,我们的研究为TRIM47在CDO1介导的肝癌细胞铁凋亡中的作用机制提供了新的见解，强调其作为肝癌治疗方法的潜在候选靶点的价值。
