Trabid inhibits hepatocellular carcinoma growth and metastasis by cleaving RNF8-induced K63 ubiquitination of Twist1.
Trabid inhibits hepatocellular carcinoma growth and metastasis by cleaving RNF8-induced K63 ubiquitination of Twist1.
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Trabid 通过裂解 RNF8 诱导的 Twist1 K63 泛素化来抑制肝细胞癌生长和转移
DOI：
10.1038/s41418-018-0119-2
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发表时间：
2019-01
影响因子：
12.4
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Zhu Y;Qu C;Hong X;Jia Y;Lin M;Luo Y;Lin F;Xie X;Xie X;Huang J;Wu Q;Qiu X;Piao D;Xing Y;Yu T;Lu Y;Huang Q;Yu C;Jin J;Zhang Z
Traf结合结构域(TRABID)是近年来发现的一种去泛素化酶，可激活Wnt/β-连环蛋白信号通路。然而，曲贝德在包括肝细胞癌在内的肿瘤中的作用以及控制其活性的潜在机制仍然知之甚少。在此，我们报道了与正常对照相比，TraBid在肝癌肿瘤样本和细胞系中的表达显著下调，其表达水平与肝癌的病理分级、复发和转移呈负相关。TRABID在肿瘤细胞中的重新表达显著降低了肝细胞癌的进展和肺转移。曲贝德对肝细胞癌发生的影响至少部分是通过调节Twist1活性来实现的。在机制上，TRABID与Twist1形成一个复合体，并特异性地从Twist1上切割RNF8诱导的K63连接的多泛素链，这增强了Twist1与β-TrCP1的结合，并允许Twist1随后的K48连接的泛素化。TRABID的敲除增加了K63连接的泛素化，但取消了K48连接的泛素化和Twist1的降解，从而促进了肝癌的生长和转移。有趣的是，Twist1负调控Trabid的启动子活性，表明存在一个双负反馈环。我们的研究结果还发现，通过AKT介导的Ser78/Thr117处的磷酸化激活Traid在负调控Twist1信号转导中起着至关重要的作用，这进一步为Traid调节Twist1泛素化的机制提供了洞察力。我们的结果显示，曲必得是一种以前未被认识的肝癌进展和转移的抑制因子，这为肝癌的治疗提供了新的策略。
TRAF-binding domain (Trabid), one of deubiquitination enzymes, was recently reported to activate Wnt/ β-catenin signaling pathway. However, the role of Trabid in tumors including hepatocellular carcinoma (HCC) and the underlying mechanisms controlling its activity remain poorly understood. Here, we report that Trabid is significantly downregulated in HCC tumor samples and cell lines compared with normal controls and that its expression level is negatively correlated with HCC pathological grading, recurrence, and metastasis. The reintroduction of Trabid expression in tumor cells significantly decreases HCC progression as well as pulmonary metastasis. The effect of Trabid on HCC development occurs at least partially through regulation of Twist1 activity. Mechanistically, Trabid forms a complex with Twist1 and specifically cleaves RNF8-induced K63-linked poly-ubiquitin chains from Twist1, which enhances the association of Twist1 with β-TrCP1 and allows for subsequent K48-linked ubiquitination of Twist1. Knockdown of Trabid increases K63-linked ubiquitination, but abrogates K48-linked ubiquitination and degradation of Twist1, thus enhancing HCC growth and metastasis. Interestingly, Twist1 negatively regulates the promoter activity of Trabid, indicating that a double-negative feedback loop exists. Our findings also identify an essential role for activation of Trabid by AKT-mediated phosphorylation at Ser78/Thr117 in negatively regulating Twist1 signaling, which further provides insights into the mechanisms by which Trabid regulates Twist1 ubiquitination. Our results reveal that Trabid is a previously unrecognized inhibitor of HCC progression and metastasis, which sheds light on new strategies for HCC treatment.
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影响因子：
4.5
作者：
Fernando MD;Kounatidis I;Ligoxygakis P
通讯作者：
Ligoxygakis P
影响因子：
7.3
作者：
Iliopoulos D;Polytarchou C;Hatziapostolou M;Kottakis F;Maroulakou IG;Struhl K;Tsichlis PN
通讯作者：
Tsichlis PN
影响因子：
24.5
作者：
Hong, Xuehui;Song, Ruipeng;Zhang, Zhiyong
通讯作者：
Zhang, Zhiyong
影响因子：
11.2
作者：
Li CW;Xia W;Lim SO;Hsu JL;Huo L;Wu Y;Li LY;Lai CC;Chang SS;Hsu YH;Sun HL;Kim J;Yamaguchi H;Lee DF;Wang H;Wang Y;Chou CK;Hsu JM;Lai YJ;LaBaff AM;Ding Q;Ko HW;Tsai FJ;Tsai CH;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
DOI：
10.1097/mco.0b013e32833781b5
发表时间：
2010-05
影响因子：
3.1
作者：
McCarthy JJ;Esser KA
通讯作者：
Esser KA