FBXO28 suppresses liver cancer invasion and metastasis by promoting PKA-dependent SNAI2 degradation

Oncogene. 2023 Sep;42(39):2878-2891. doi: 10.1038/s41388-023-02809-0. Epub 2023 Aug 18.

Abstract

FBXO28 is a member of F-box proteins that are the substrate receptors of SCF (SKP1, CULLIN1, F-box protein) ubiquitin ligase complexes. Despite the implications of its role in cancer, the function of FBXO28 in epithelial-mesenchymal transition (EMT) process and metastasis for cancer remains largely unknown. Here, we report that FBXO28 is a critical negative regulator of migration, invasion and metastasis in human hepatocellular carcinoma (HCC) in vitro and in vivo. FBXO28 expression is upregulated in human epithelial cancer cell lines relative to mesenchymal counterparts. Mechanistically, by directly binding to SNAI2, FBXO28 functions as an E3 ubiquitin ligase that targets the substrate for degradation via ubiquitin proteasome system. Importantly, we establish a cooperative function for PKA in FBXO28-mediated SNAI2 degradation. In clinical HCC specimens, FBXO28 protein levels positively whereas negatively correlate with PKAα and SNAI2 levels, respectively. Low FBXO28 or PRKACA expression is associated with poor prognosis of HCC patients. Together, these findings elucidate the novel function of FBXO28 as a critical inhibitor of EMT and metastasis in cancer and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human aggressive HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / pathology
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Epithelial-Mesenchymal Transition / genetics
  • F-Box Proteins* / genetics
  • F-Box Proteins* / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / pathology
  • Neoplasm Metastasis
  • SKP Cullin F-Box Protein Ligases / genetics
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism
  • Ubiquitins / metabolism

Substances

  • F-Box Proteins
  • Ubiquitins
  • FBXO28 protein, human
  • SKP Cullin F-Box Protein Ligases
  • SNAI2 protein, human
  • Snail Family Transcription Factors