Arginine methylation-dependent TRIM47 stability mediated by CARM1 promotes the metastasis of hepatocellular carcinoma.

IF 6.1 2区生物学 Q1 CELL BIOLOGY Cell Death Discovery Pub Date : 2024-11-20 DOI:10.1038/s41420-024-02244-4

Yuzhe Tang, Xiang Meng, Xia Luo, Wentao Yao, Li Tian, Zijian Zhang, Yuan Zhao, Juan Xiao, Haichuan Zhu, Jia Hu

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Abstract

The tripartite motif (TRIM) protein family has been shown to play important roles in the occurrence and development of various tumors. However, the biological functions of TRIM47 and its regulatory mechanism in hepatocellular carcinoma (HCC) remain unexplored. Here, we showed that TRIM47 was upregulated in HCC tissues compared with adjacent normal tissues, especially at advanced stages, and associated with poor prognosis in HCC patients. Functional studies demonstrated that TRIM47 enhanced the migration and invasion ability of HCC cells in vitro and in vivo. Mechanistically, TRIM47 promotes HCC metastasis through interacting with SNAI1 and inhibiting its degradation by proteasome. Moreover, TRIM47 was di-methylated by CARM1 at its arginine 210 (R210) and arginine 582 (R582), which protected TRIM47 from the ubiquitination and degradation mediated by E3 ubiquitin ligase complex CRL4^CRBN. Collectively, our study reveals a pro-metastasis role of TRIM47 in HCC, unveils a unique mechanism controlling TRIM47 stability by CARM1 mediated arginine methylation, and highlights the role of the CARM1-CRL4^CRBN-TRIM47-SNAI1 axis in HCC metastasis. This work may provide potential therapeutic targets for metastatic HCC treatment.

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CARM1 介导的精氨酸甲基化依赖性 TRIM47 稳定性促进了肝细胞癌的转移。

三方基序（TRIM）蛋白家族已被证明在各种肿瘤的发生和发展中发挥重要作用。然而，TRIM47在肝细胞癌（HCC）中的生物学功能及其调控机制仍有待探索。在这里，我们发现与邻近的正常组织相比，TRIM47在HCC组织中上调，尤其是在晚期，并且与HCC患者的不良预后相关。功能研究表明，TRIM47增强了HCC细胞在体外和体内的迁移和侵袭能力。从机理上讲，TRIM47通过与SNAI1相互作用并抑制其被蛋白酶体降解来促进HCC转移。此外，TRIM47在其精氨酸210（R210）和精氨酸582（R582）处被CARM1二甲基化，从而保护TRIM47不被E3泛素连接酶复合物CRL4CRBN介导的泛素化和降解。总之，我们的研究揭示了 TRIM47 在 HCC 中的促转移作用，揭示了 CARM1 介导的精氨酸甲基化控制 TRIM47 稳定性的独特机制，并强调了 CARM1-CRL4CRBN-TRIM47-SNAI1 轴在 HCC 转移中的作用。这项工作可能会为转移性 HCC 的治疗提供潜在的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.