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SPOP promotes CREB5 ubiquitination to inhibit MET signaling in liver cancer

De-Ao Gong1, Peng Zhou1, Wen-Yi Chang1

  • 1Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China.

Biochimica Et Biophysica Acta. Molecular Cell Research
|November 23, 2023
PubMed

Insights

Speckle-type POZ protein (SPOP) suppresses liver cancer metastasis by regulating cAMP response element binding 5 (CREB5) ubiquitination. Disruptions in this SPOP-CREB5 interaction activate MET signaling, promoting cancer spread.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Liver cancer is a leading cause of cancer mortality worldwide.
  • Metastasis is a primary driver of treatment failure and mortality in liver cancer patients.
  • Speckle-type POZ protein (SPOP) is a tumor suppressor in liver cancer, but its role in metastasis is unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism of SPOP in liver cancer metastasis.
  • To identify novel SPOP substrates involved in liver cancer progression.
  • To investigate the SPOP-CREB5-MET signaling axis in hepatoma cells.

Main Methods:

  • Co-immunoprecipitation assays to identify SPOP-CREB5 interaction.
  • Ubiquitination assays to detect CREB5 modification at K432.
  • In vitro and in vivo assays to assess hepatoma cell metastasis.
  • Analysis of SPOP mutant effects on CREB5 and MET signaling.

Main Results:

  • cAMP response element binding 5 (CREB5) was identified as a novel substrate of SPOP in liver cancer.
  • SPOP mediates non-degradative K63-polyubiquitination of CREB5, inhibiting MET activation.
  • A liver cancer-associated SPOP mutant (S119N) impairs CREB5 ubiquitination, leading to MET pathway activation and enhanced metastasis.
  • Disruption of the SPOP-CREB5 interaction promotes hepatoma cell migration and invasion.

Conclusions:

  • The SPOP-CREB5-MET signaling axis is functionally significant in regulating liver cancer metastasis.
  • Targeting the SPOP-CREB5 interaction may offer a therapeutic strategy for liver cancer.
  • Understanding SPOP's role in CREB5 ubiquitination provides insights into liver cancer progression.
Keywords:
CREB5Liver cancerMETSPOPUbiquitination

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