ST3GAL5-catalyzed gangliosides inhibit TGF-β-induced epithelial-mesenchymal transition via TβRI degradation

EMBO J. 2023 Jan 16;42(2):e110553. doi: 10.15252/embj.2021110553. Epub 2022 Dec 12.

Abstract

Epithelial-mesenchymal transition (EMT) is pivotal in the initiation and development of cancer cell metastasis. We observed that the abundance of glycosphingolipids (GSLs), especially ganglioside subtypes, decreased significantly during TGF-β-induced EMT in NMuMG mouse mammary epithelial cells and A549 human lung adenocarcinoma cells. Transcriptional profiling showed that TGF-β/SMAD response genes and EMT signatures were strongly enriched in NMuMG cells, along with depletion of UDP-glucose ceramide glucosyltransferase (UGCG), the enzyme that catalyzes the initial step in GSL biosynthesis. Consistent with this finding, genetic or pharmacological inhibition of UGCG promoted TGF-β signaling and TGF-β-induced EMT. UGCG inhibition promoted A549 cell migration, extravasation in the zebrafish xenograft model, and metastasis in mice. Mechanistically, GSLs inhibited TGF-β signaling by promoting lipid raft localization of the TGF-β type I receptor (TβRI) and by increasing TβRI ubiquitination and degradation. Importantly, we identified ST3GAL5-synthesized a-series gangliosides as the main GSL subtype involved in inhibition of TGF-β signaling and TGF-β-induced EMT in A549 cells. Notably, ST3GAL5 is weakly expressed in lung cancer tissues compared to adjacent nonmalignant tissues, and its expression correlates with good prognosis.

Keywords: ST3GAL5; UDP-glucose ceramide glucosyltransferase; epithelial-mesenchymal transition; glycosphingolipids; transforming growth factor-β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalysis
  • Cell Line, Tumor
  • Cell Movement
  • Epithelial-Mesenchymal Transition / genetics
  • Gangliosides
  • Glycosphingolipids
  • Humans
  • Lung Neoplasms* / metabolism
  • Mice
  • Transforming Growth Factor beta* / metabolism
  • Zebrafish / metabolism

Substances

  • Transforming Growth Factor beta
  • Gangliosides
  • Glycosphingolipids

Associated data

  • GEO/GSE192691