CUL4A exhibits tumor-suppressing role via regulation of HUWE1-mediated SMAD3 intracellular shuttling

Danek V, Tureckova J, Hübner K, Erlenbach-Wünsch K, Baranova P, Dobes J, Balounova J, Simova M, Novosadova V, Madureira Trufen CE, Prochazkova M, Talacko P, Harant K, Barinka C, Beck IM, Schneider-Stock R, Sedlacek R, Prochazka J (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Cancer Letters Elsevier

Book Volume: 621

Article Number: 217663

DOI: 10.1016/j.canlet.2025.217663

Abstract

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.

Authors with CRIS profile

Kerstin Hübner Professur für Experimentelle Tumorpathologie Katharina Erlenbach-Wünsch Medizinische Fakultät Regine Schneider-Stock Professur für Experimentelle Tumorpathologie

Involved external institutions

Institute of Molecular Genetics of the ASCR / Ústav molekulární genetiky AV ČR CZ Czech Republic (CZ) Czech Academy of Sciences, Institute of Biotechnology / BTÚ AV ČR, Biotechnologický ústav AV ČR CZ Czech Republic (CZ) Univerzita Karlova v Praze / Charles University in Prague CZ Czech Republic (CZ)

How to cite

APA:

Danek, V., Tureckova, J., Hübner, K., Erlenbach-Wünsch, K., Baranova, P., Dobes, J.,... Prochazka, J. (2025). CUL4A exhibits tumor-suppressing role via regulation of HUWE1-mediated SMAD3 intracellular shuttling. Cancer Letters, 621. https://doi.org/10.1016/j.canlet.2025.217663

MLA:

Danek, Veronika, et al. "CUL4A exhibits tumor-suppressing role via regulation of HUWE1-mediated SMAD3 intracellular shuttling." Cancer Letters 621 (2025).

BibTeX: Download