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Peer-reviewedCC BY-NCCancer science

NEDD4 Promotes Hepatocellular Carcinoma Progression Through Ubiquitin-Dependent Degradation of EPHB6.

  • Guowei Zhang1,2,3
  • Mengxuan Ji1,2
  • Zhiyi Liu1,2
  • Jiawei Xu1,2
  • Qinghe Hu1,2
  • Xue Zhang1,2
  • Jie Qiu1,2
  • Kai Wu1,2
  • Bin Zhang1,2
  • Yi He4
  • Hengliang Shi1,2,5,6
6 affiliations
  1. 1Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, China.
  2. 2General Surgery Department, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
  3. 3Department of General Surgery, Xuzhou Central Hospital, Southeast University, Xuzhou, China.
  4. 4Experimental Teaching Center for Basic Surgery, the First Clinical Medical College, Xuzhou Medical University, Xuzhou, China.
  5. 5Jiangsu Key Laboratory of Organ Transplantation and Transplant Immunology, Xuzhou, China.
  6. 6Center for Sci-Tech Innovation and Public Service, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
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Abstract

Neural precursor cell expressed developmentally down-regulated 4 (NEDD4) has been implicated in the progression of various human malignancies, including hepatocellular carcinoma (HCC). However, the relationship between NEDD4's ubiquitin ligase activity and the motility of HCC cells remains unclear. We investigated the significance of the NEDD4/EPHB6 (erythropoietin-producing hepatocyte B6) axis in driving epithelial-mesenchymal transition (EMT) progression in HCC. In this study, we investigated the role of the HECT-type E3 ubiquitin ligase NEDD4 in HCC progression and identified its downstream substrate through integrated bioinformatic screening, protein-level validation, and NEDD4 immunoprecipitation coupled with mass spectrometry. The regulatory relationship between NEDD4 and EPHB6 was examined using ubiquitination assays, protein stability analysis, and functional rescue experiments. Potential downstream signaling changes associated with the NEDD4-EPHB6 axis were further examined through pathway analysis and molecular validation. NEDD4 silencing suppressed, whereas its overexpression enhanced HCC cell invasion and migration. Mechanistically, NEDD4 functioned as an E3 ubiquitin ligase that promoted Lys48-linked polyubiquitination and proteasomal degradation of erythropoietin-producing hepatocyte B6 (EPHB6), resulting in reduced EPHB6 protein abundance without altering EPHB6 mRNA levels. Disruption of the NEDD4-EPHB6 axis attenuated EMT, which was further validated in a xenograft mouse model. Moreover, NEDD4 protein expression was inversely correlated with EPHB6 levels in clinical HCC tissues. In summary, our study identifies the NEDD4-EPHB6 axis as a previously unrecognized regulator of EMT-associated malignant progression in HCC and demonstrates its association with activation of TGF-β/SMAD2/3 signaling. This study provides new mechanistic insight into how post-translational regulation of membrane-associated proteins controls HCC progression.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026nedd4,
  title = {{NEDD4 Promotes Hepatocellular Carcinoma Progression Through Ubiquitin-Dependent Degradation of EPHB6.}},
  author = {Guowei Zhang and Mengxuan Ji and Zhiyi Liu and Jiawei Xu and Qinghe Hu and Xue Zhang and Jie Qiu and Kai Wu and Bin Zhang and Yi He and Hengliang Shi},
  journal = {Cancer science},
  year = {2026},
  month = oct,
  doi = {10.1111/cas.70573},
  url = {https://europepmc.org/article/MED/42952244},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - NEDD4 Promotes Hepatocellular Carcinoma Progression Through Ubiquitin-Dependent Degradation of EPHB6.
AU  - Guowei Zhang
AU  - Mengxuan Ji
AU  - Zhiyi Liu
AU  - Jiawei Xu
AU  - Qinghe Hu
AU  - Xue Zhang
AU  - Jie Qiu
AU  - Kai Wu
AU  - Bin Zhang
AU  - Yi He
AU  - Hengliang Shi
PY  - 2026
DA  - 2026/10/28
JO  - Cancer science
DO  - 10.1111/cas.70573
UR  - https://europepmc.org/article/MED/42952244
AB  - Neural precursor cell expressed developmentally down-regulated 4 (NEDD4) has been implicated in the progression of various human malignancies, including hepatocellular carcinoma (HCC). However, the relationship between NEDD4's ubiquitin ligase activity and the motility of HCC cells remains unclear. We investigated the significance of the NEDD4/EPHB6 (erythropoietin-producing hepatocyte B6) axis in driving epithelial-mesenchymal transition (EMT) progression in HCC. In this study, we investigated the role of the HECT-type E3 ubiquitin ligase NEDD4 in HCC progression and identified its downstream substrate through integrated bioinformatic screening, protein-level validation, and NEDD4 immunoprecipitation coupled with mass spectrometry. The regulatory relationship between NEDD4 and EPHB6 was examined using ubiquitination assays, protein stability analysis, and functional rescue experiments. Potential downstream signaling changes associated with the NEDD4-EPHB6 axis were further examined through pathway analysis and molecular validation. NEDD4 silencing suppressed, whereas its overexpression enhanced HCC cell invasion and migration. Mechanistically, NEDD4 functioned as an E3 ubiquitin ligase that promoted Lys48-linked polyubiquitination and proteasomal degradation of erythropoietin-producing hepatocyte B6 (EPHB6), resulting in reduced EPHB6 protein abundance without altering EPHB6 mRNA levels. Disruption of the NEDD4-EPHB6 axis attenuated EMT, which was further validated in a xenograft mouse model. Moreover, NEDD4 protein expression was inversely correlated with EPHB6 levels in clinical HCC tissues. In summary, our study identifies the NEDD4-EPHB6 axis as a previously unrecognized regulator of EMT-associated malignant progression in HCC and demonstrates its association with activation of TGF-β/SMAD2/3 signaling. This study provides new mechanistic insight into how post-translational regulation of membrane-associated proteins controls HCC progression.
SN  - 1347-9032
SN  - 1349-7006
ER  -