CUL4A exhibits tumor-suppressing role via regulation of HUWE1-mediated SMAD3 intracellular shuttling
Language English Country Ireland Media print-electronic
Document type Journal Article
PubMed
40120800
DOI
10.1016/j.canlet.2025.217663
PII: S0304-3835(25)00229-0
Knihovny.cz E-resources
- Keywords
- CUL4A, Colorectal cancer, HUWE1, Ubiquitination,
- MeSH
- HCT116 Cells MeSH
- Colorectal Neoplasms * pathology genetics metabolism MeSH
- Cullin Proteins * metabolism genetics MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Tumor Suppressor Proteins * metabolism genetics MeSH
- Smad3 Protein * metabolism genetics MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Wnt Signaling Pathway MeSH
- Ubiquitination MeSH
- Ubiquitin-Protein Ligases * metabolism genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- CUL4A protein, human MeSH Browser
- HUWE1 protein, human MeSH Browser
- Cullin Proteins * MeSH
- Tumor Suppressor Proteins * MeSH
- Smad3 Protein * MeSH
- SMAD3 protein, human MeSH Browser
- Ubiquitin-Protein Ligases * MeSH
Changes in cellular physiology and proteomic homeostasis accompanied the initiation and progression of colorectal cancer. Thus, ubiquitination represents a central regulatory mechanism in proteome dynamics. However, the complexity of the ubiquitinating network involved in carcinogenesis remains unclear. This study revealed the tumor-suppressive role of the ubiquitin ligase Cullin4A (CUL4A) in the intestine. We showed that simultaneous loss of CUL4A and hyperactivation of the Wnt pathway promotes tumor development in the distal colon. This tumor development is caused by an accumulation of the inactive SMAD3, a TGF-β pathway mediator. Depletion of CUL4A resulted in stabilization of HUWE1, which attenuated SMAD3 function. We showed a correlation between the intracellular localization of CUL4A and colorectal cancer progression, where nuclear CUL4A localization correlates with advanced colorectal cancer progression. In summary, we identified CUL4A as an important regulator of SMAD3 signal transduction competence in a HUWE1-dependent manner and demonstrated a critical role for the crosstalk between ubiquitination and the Wnt/TGF-β signaling pathways in gastrointestinal homeostasis.
BIOCEV Proteomics Core Facility Faculty of Science Charles University Vestec 252 50 Czech Republic
Department of Cell Biology Faculty of Science Charles University 128 00 Prague Czech Republic
Institute of Pathology FAU Erlangen Nürnberg 91054 Erlangen Germany
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