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. 2025 Jul 1:621:217663.
doi: 10.1016/j.canlet.2025.217663. Epub 2025 Mar 20.

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

Veronika Danek  1 , Jolana Tureckova  1 , Kerstin Huebner  2 , Katharina Erlenbach-Wuensch  3 , Petra Baranova  4 , Jan Dobes  5 , Jana Balounova  6 , Michaela Simova  1 , Vendula Novosadova  6 , Carlos Eduardo Madureira Trufen  6 , Michaela Prochazkova  6 , Pavel Talacko  7 , Karel Harant  7 , Cyril Barinka  4 , Inken M Beck  8 , Regine Schneider-Stock  9 , Radislav Sedlacek  10 , Jan Prochazka  11
Affiliations

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

Veronika Danek et al. Cancer Lett. .

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.

Keywords: CUL4A; Colorectal cancer; HUWE1; Ubiquitination.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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