Open AccessTRIM65 triggers β-Catenin signaling via ubiquitination of Axin1 to promote hepatocellular carcinoma
Author(s) -
Yufeng Yang,
Meifang Zhang,
Tian Qing,
Chris Zhiyi Zhang
Publication year - 2017
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.206623
Subject(s) - biology , ubiquitin , gene knockdown , cancer research , ubiquitin ligase , oncogene , hepatocellular carcinoma , catenin , metastasis , regulator , signal transduction , cell culture , microbiology and biotechnology , cell , cell cycle , wnt signaling pathway , cancer , genetics , gene
Deregulation of ubiquitin ligases contribute to the malignant progression of human cancers. Tripartite motif 65 (TRIM65) belongs to E3 ubiquitin ligase and has been implicated in human diseases, but its role and clinical significance remain unknown in hepatocellular carcinoma (HCC). Here, we showed that TRIM65 expression was increased in HCC tissues and associated with poor outcomes in two independent cohorts containing 888 patients. In vitro and in vivo data demonstrated overexpression of TRIM65 promoted cell growth and tumor metastasis, whereas knockdown of TRIM65 resulted in opposite phenotypes. Further studies revealed that TRIM65 exerted oncogenic activities via ubiquitination of Axin1 to activate β-Catenin signaling pathway. TRIM65 directly bound to Axin1 and accelerated its degradation through ubiquitination. Furthermore, HMGA1 was identified as an upstream regulator of TRIM65 in HCC cells. In clinical samples, TRIM65 expression was positively correlated with the expression of HMGA1 and nuclear β-Catenin. Collectively, our data indicate that TRIM65 functions as an oncogene in HCC. The newly identified HMGA1/TRIM65/β-Catenin axis serves as a promising prognostic factor and therapeutic target.