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NEDD4 Induces K48-Linked Degradative Ubiquitination of Hepatitis B Virus X Protein and Inhibits HBV-Associated HCC

Tao Wan1, Zhao Lei1, Biao Tu1

  • 1Department of Hepatobiliary Surgery, The Third Xiangya Hospital of Central South University, Changsha, China.

Frontiers in Oncology
|March 26, 2021
PubMed

Insights

Neural precursor cell expressed developmentally downregulated gene 4 (NEDD4) suppresses hepatocellular carcinoma (HCC) by degrading the hepatitis B virus X protein (HBx). High NEDD4 expression improves patient survival in HBV-associated HCC.

Area of Science:

  • Oncology
  • Virology
  • Molecular Biology

Background:

  • Neural precursor cell expressed developmentally downregulated gene 4 (NEDD4) has dual roles in cancer.
  • Its function in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) is unclear.

Purpose of the Study:

  • To investigate the role and mechanism of NEDD4 in HBV-associated HCC.
  • To analyze NEDD4 expression in HCC tissues and its correlation with patient outcomes.

Main Methods:

  • Analyzed NEDD4 expression in 199 HCC specimens.
  • Assessed NEDD4's effect on proliferation, migration, and invasion in HCC cell lines.
  • Investigated the interaction between NEDD4 and HBV X protein (HBx).
  • Determined NEDD4's role in HBx degradation via ubiquitination.

Main Results:

  • NEDD4 expression was not linked to HBV exposure but high NEDD4 correlated with better overall survival (OS) and progression-free survival (PFS) in HBV-associated HCC.
  • NEDD4 upregulation inhibited proliferation, migration, and invasion in HBV-related HCC cells.
  • NEDD4 interacts with HBx and promotes its degradation through K48-linked ubiquitination, reversing HBx-induced proliferation and mobility.

Conclusions:

  • NEDD4 acts as a tumor suppressor in HBV-associated HCC.
  • NEDD4 exerts its tumor-suppressive function by degrading HBx via the ubiquitin-proteasome pathway.
  • This study provides novel insights into NEDD4's function in HBV-related liver cancer.
Keywords:
HBV-associated HCCHBxNEDD4hepatocellular carcinomaubiquitin-proteasome pathway

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