2. Academic Validation
  3. SPOP promotes CREB5 ubiquitination to inhibit MET signaling in liver cancer

SPOP promotes CREB5 ubiquitination to inhibit MET signaling in liver cancer

  • Biochim Biophys Acta Mol Cell Res. 2023 Nov 22;1871(2):119642. doi: 10.1016/j.bbamcr.2023.119642.
De-Ao Gong 1,  Peng Zhou 1,  Wen-Yi Chang 1,  Jia-Yao Yang 1,  Yan-Lai Zhang 1,  Ai-Long Huang 1,  Ni Tang 2,  Kai Wang 3
Affiliations

Affiliations

  • 1 Key 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.
  • 2 Key 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. Electronic address: [email protected].
  • 3 Key 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. Electronic address: [email protected].
PMID: 37996058 DOI: 10.1016/j.bbamcr.2023.119642
Abstract

Liver Cancer is ranked as the sixth most prevalent from of malignancy globally and stands as the third primary contributor to cancer-related mortality. Metastasis is the main reason for liver Cancer treatment failure and patient deaths. Speckle-type POZ protein (SPOP) serves as a crucial substrate junction protein within the cullin-RING E3 ligase complex, acting as a significant tumor suppressor in liver Cancer. Nevertheless, the precise molecular mechanism underlying the role of SPOP in liver Cancer metastasis remain elusive. In the current study, we identified cAMP response element binding 5 (CREB5) as a novel SPOP substrate in liver Cancer. SPOP facilitates non-degradative K63-polyubiquitination of CREB5 on K432 site, consequently hindering its capacity to activate receptor tyrosine kinase MET. Moreover, liver cancer-associated SPOP mutant S119N disrupts the SPOP-CREB5 interactions and impairs the ubiquitination of CREB5.This disruption ultimately leads to the activation of the MET signaling pathway and enhances metastatic properties of hepatoma cells both in vitro and in vivo. In conclusion, our findings highlight the functional significance of the SPOP-CREB5-MET axis in liver Cancer metastasis.

Keywords

CREB5; Liver cancer; MET; SPOP; Ubiquitination.

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