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Deubiquitinase USP39 and E3 ligase TRIM26 balance the level of ZEB1 ubiquitination and thereby determine the progression of hepatocellular carcinoma
- Source :
- Cell Death and Differentiation
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
Abstract
- Emerging evidence suggests that USP39 plays an important role in the development of hepatocellular carcinoma (HCC). However, the molecular mechanism by which USP39 promotes HCC progression has not been well defined, especially regarding its putative ubiquitination function. Zinc-finger E-box-binding homeobox 1 (ZEB1) is a crucial inducer of epithelial-to-mesenchymal transition (EMT) to promote tumor proliferation and metastasis, but the regulatory mechanism of ZEB1 stability in HCC remains enigmatic. Here, we reveal that USP39 is highly expressed in human HCC tissues and correlated with poor prognosis. Moreover, USP39 depletion inhibits HCC cell proliferation and metastasis by promoting ZEB1 degradation. Intriguingly, deubiquitinase USP39 has a direct interaction with the E3 ligase TRIM26 identified by co-immunoprecipitation assays and immunofluorescence staining assays. We further demonstrate that TRIM26 is lowly expressed in human HCC tissues and inhibits HCC cell proliferation and migration. TRIM26 promotes the degradation of ZEB1 protein by ubiquitination in HCC. Deubiquitinase USP39 and E3 ligase TRIM26 function in an antagonistic pattern, but not a competitive pattern, and play key roles in controlling ZEB1 stability to determine the HCC progression. In summary, our data reveal a previously unknown mechanism that USP39 and TRIM26 balance the level of ZEB1 ubiquitination and thereby determine HCC cell proliferation and migration. This novel mechanism may provide new approaches to target treatment for inhibiting HCC development by restoring TRIM26 or suppressing USP39 expression in HCC cases with high ZEB1 protein levels.
- Subjects :
- Carcinoma, Hepatocellular
Ubiquitin-Protein Ligases
Mice, Nude
Article
Metastasis
Deubiquitinating enzyme
Tripartite Motif Proteins
Prognostic markers
Mice
Ubiquitin
Cell Line, Tumor
medicine
Animals
Humans
neoplasms
Molecular Biology
biology
Cell growth
Liver Neoplasms
Ubiquitination
Zinc Finger E-box-Binding Homeobox 1
Cell Biology
medicine.disease
Survival Analysis
digestive system diseases
Gene regulation
Ubiquitin ligase
Hepatocellular carcinoma
Disease Progression
biology.protein
Cancer research
Homeobox
Ubiquitin-Specific Proteases
Function (biology)
Subjects
Details
- ISSN :
- 14765403 and 13509047
- Volume :
- 28
- Database :
- OpenAIRE
- Journal :
- Cell Death & Differentiation
- Accession number :
- edsair.doi.dedup.....9ae6b07aa6f400a6cb145e2d4de74e80