Trabid inhibits hepatocellular carcinoma growth and metastasis by cleaving RNF8-induced K63 ubiquitination of Twist1.

Cell Death and Differentiation
Yuekun ZhuZhiyong Zhang

Abstract

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 ...Continue Reading

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Citations

May 27, 2020·The Journal of Experimental Medicine·Qingxin ZhouZhiyong Zhang
Dec 31, 2019·Frontiers of Medicine·Jiansen DuLingqiang Zhang
Nov 2, 2019·Essays in Biochemistry·Guillem LambiesVíctor M Díaz
Aug 6, 2020·Molecular Cancer Research : MCR·Jingyu KuangLingyun Zhu
Jan 1, 2021·The Journal of Biological Chemistry·Lee D HarrisJulien D F Licchesi
Jan 23, 2021·Proceedings of the National Academy of Sciences of the United States of America·Virginia De CesareSatpal Virdee
Jan 14, 2021·International Journal of Molecular Sciences·Emma I Kane, Donald E Spratt
Jan 1, 2021·BioMed Research International·Liang-Chun YinLi-Xin Liu
Jan 12, 2021·The Journal of Biological Chemistry·Lee D HarrisJulien D F Licchesi
Apr 16, 2021·The Journal of Biological Chemistry·Lee D HarrisJulien D F Licchesi

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Methods Mentioned

BETA
surgical resection
transfection
xenograft
PCR
bioluminescence imaging
ubiquitination
co-IP
pulldown
deubiquitination
immunoprecipitation

Software Mentioned

Scansite
Graphpad Prism
Trabid
SPSS

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