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RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner

Kyle Lewis1,2,3, Leila Valanejad1, Ashley Cast1

  • 1Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Molecular and Cellular Biology
|June 1, 2017
PubMed

Insights

CUGBP1 dephosphorylation at Ser302 activates its translation, promoting liver cancer. Gankyrin targets this form for degradation, a key event in liver cancer development. This study reveals CUGBP1 as a crucial tumor suppressor.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Oncology

Background:

  • Mechanisms underlying liver cancer remain incompletely understood.
  • CUGBP1, an RNA binding protein, has identified tumor suppressor activities.
  • Dephosphorylation at Ser302 activates CUGBP1's translational activity.

Purpose of the Study:

  • To elucidate the role of CUGBP1 phosphorylation in liver cancer.
  • To investigate the mechanism of CUGBP1 neutralization in liver tumorigenesis.
  • To identify factors contributing to the reduction of CUGBP1 in liver cancer.

Main Methods:

  • Generation of CUGBP1-S302A knock-in mice.
  • Diethylnitrosamine (DEN) treatment to induce liver cancer.
  • Investigation of gankyrin (Gank) binding and degradation pathways.
  • Generation of mice with liver-specific deletion of Gank.

Main Results:

  • Reduced translational activity of CUGBP1 leads to fatty liver in S302A mice.
  • DEN-treated S302A mice exhibit more severe liver cancer with CUGBP1 elimination.
  • Gank preferentially binds and degrades dephosphorylated or S302A mutant CUGBP1.
  • Liver-specific Gank deletion protects CUGBP1 from degradation, reducing tumor suppressor loss.

Conclusions:

  • Dephosphorylated CUGBP1 (de-ph-S302-CUGBP1) functions as a tumor suppressor.
  • Gank-induced degradation of CUGBP1 via the ubiquitin-proteasome system (UPS) is critical for liver cancer development.
  • Reduced CUGBP1 levels correlate with liver cancer in both animal models and human pediatric liver cancer patients.
Keywords:
C/EBPC/EBPβCUGBP1HBLHCCgankyrinphosphorylation

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