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DAPK enhances DDX20 protein stability via suppression of TRIM25-mediated ubiquitination-based DDX20 degradation

Yan Ye1,2,3, Xiuli Zhang1,2, Chenyi Wang4

  • 1College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, Fujian, China.

Cancer Cell International
|November 18, 2024
PubMed

Insights

Death-associated protein kinase (DAPK) stabilizes DDX20 by inhibiting TRIM25-mediated degradation, suppressing hepatocellular carcinoma (HCC) cell invasion. This reveals a new DAPK-TRIM25-DDX20 axis for HCC drug development.

Area of Science:

  • Molecular oncology
  • Cell signaling pathways

Background:

  • The DAPK-DDX20 axis shows anti-cancer activity in hepatocellular carcinoma (HCC) by inhibiting CDC42 GTPase activity, reducing cancer cell invasion and migration.
  • DAPK enhances DDX20 protein levels by suppressing its degradation, but the precise mechanism remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which DAPK regulates DDX20 stability.
  • To identify the E3 ubiquitin ligase responsible for DDX20 degradation.
  • To investigate the role of TRIM25 in the DAPK-DDX20 signaling pathway and its implications in HCC.

Main Methods:

  • Investigated DDX20 degradation via the ubiquitin-proteasome pathway.
  • Identified TRIM25 as the E3 ubiquitin ligase for DDX20 using binding and ubiquitination assays.
  • Analyzed the formation of a ternary complex involving DAPK, TRIM25, and DDX20.
  • Utilized shRNA to assess the functional impact of TRIM25 knockdown on cell migration and invasion.

Main Results:

  • DDX20 is degraded through the ubiquitin-proteasome pathway, with TRIM25 identified as the specific E3 ubiquitin ligase.
  • TRIM25 ubiquitinates DDX20 in the 1-244 amino acid region, promoting its proteasomal degradation.
  • DAPK interacts with the 1-244 region of DDX20, inhibiting ubiquitination and enhancing DDX20 stability.
  • DAPK, TRIM25, and DDX20 form a ternary complex; TRIM25 knockdown disrupts the DAPK-DDX20 complex.
  • TRIM25 functions as an oncogene in liver cancer, as its silencing inhibits cell migration and invasion.

Conclusions:

  • TRIM25 mediates the proteasomal degradation of DDX20, and DAPK stabilizes DDX20 by inhibiting this process.
  • The DAPK-TRIM25-DDX20 interaction reveals a novel regulatory mechanism in HCC.
  • TRIM25 acts as an oncogene in liver cancer, and targeting the DAPK-TRIM25-DDX20 axis offers potential therapeutic strategies for HCC.
Keywords:
DAPKDDX20HCCTRIM25Ubiquitination

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