TRIM65 triggers β-catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma.

Publisher: Company of Biologists Country of Publication: England NLM ID: 0052457 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1477-9137 (Electronic) Linking ISSN: 00219533 NLM ISO Abbreviation: J Cell Sci Subsets: MEDLINE

Publication: Cambridge : Company of Biologists
Original Publication: London.

Signal Transduction* ; Ubiquitination*; Axin Protein/*metabolism ; Carcinoma, Hepatocellular/*metabolism ; Liver Neoplasms/*metabolism ; Tripartite Motif Proteins/*metabolism ; Ubiquitin-Protein Ligases/*metabolism ; beta Catenin/*metabolism; Animals ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation/genetics ; Gene Expression Regulation, Neoplastic ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Male ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Metastasis ; Transcription, Genetic ; Treatment Outcome ; Tripartite Motif Proteins/genetics ; Ubiquitin-Protein Ligases/genetics ; Up-Regulation/genetics

Deregulation of ubiquitin ligases contributes to the malignant progression of human cancers. Tripartite motif-containing protein 65 (TRIM65) is an E3 ubiquitin ligase and has been implicated in human diseases, but its role and clinical significance in hepatocellular carcinoma (HCC) remain unknown. Here, we showed that TRIM65 expression was increased in HCC tissues and associated with poor outcome in two independent cohorts containing 888 patients. In vitro and in vivo data demonstrated that 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 ubiquitylation of Axin1 to activate the β-catenin signaling pathway. TRIM65 directly bound to Axin1 and accelerated its degradation through ubiquitylation. 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.
Competing Interests: Competing interestsThe authors declare no competing or financial interests.
(© 2017. Published by The Company of Biologists Ltd.)

Keywords: Axin1; HMGA1; Hepatocellular carcinoma; TRIM65; β-catenin

0 (AXIN1 protein, human)
0 (Axin Protein)
0 (Tripartite Motif Proteins)
0 (beta Catenin)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
EC 6.3.2.- (TRIM65 protein, human)

Date Created: 20170730 Date Completed: 20180605 Latest Revision: 20220321

20240829

10.1242/jcs.206623

28754688