CUL4A exhibits tumor-suppressing role via regulation of HUWE1-mediated SMAD3 intracellular shuttling
Jazyk angličtina Země Irsko Médium print-electronic
Typ dokumentu časopisecké články
PubMed
40120800
DOI
10.1016/j.canlet.2025.217663
PII: S0304-3835(25)00229-0
Knihovny.cz E-zdroje
- Klíčová slova
- CUL4A, Colorectal cancer, HUWE1, Ubiquitination,
- MeSH
- HCT116 buňky MeSH
- kolorektální nádory * patologie genetika metabolismus MeSH
- kulinové proteiny * metabolismus genetika MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové supresorové proteiny * metabolismus genetika MeSH
- protein Smad3 * metabolismus genetika MeSH
- regulace genové exprese u nádorů MeSH
- signální dráha Wnt MeSH
- ubikvitinace MeSH
- ubikvitinligasy * metabolismus genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- CUL4A protein, human MeSH Prohlížeč
- HUWE1 protein, human MeSH Prohlížeč
- kulinové proteiny * MeSH
- nádorové supresorové proteiny * MeSH
- protein Smad3 * MeSH
- SMAD3 protein, human MeSH Prohlížeč
- ubikvitinligasy * 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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