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

AI Article Synopsis

  • * The study found that the enzyme UDP-glucose ceramide glucosyltransferase (UGCG), which is involved in GSL biosynthesis, decreased during EMT, and either genetically or pharmacologically inhibiting UGCG enhanced TGF-β signaling and promoted cell migration and metastasis in various models.
  • * Specific gangliosides synthesized by the enzyme ST3GAL5 were identified as key players that inhibit TGF-

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9841337PMC
http://dx.doi.org/10.15252/embj.2021110553DOI Listing

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