PUBLICATION
ST3GAL5-catalyzed gangliosides inhibit TGF-β-induced epithelial-mesenchymal transition via TβRI degradation
- Authors
- Zhang, J., van der Zon, G., Ma, J., Mei, H., Cabukusta, B., Agaser, C.C., Madunić, K., Wuhrer, M., Zhang, T., Ten Dijke, P.
- ID
- ZDB-PUB-221213-8
- Date
- 2022
- Source
- The EMBO journal 42(2): e110553 (Journal)
- Registered Authors
- Keywords
- ST3GAL5, UDP-glucose ceramide glucosyltransferase, epithelial-mesenchymal transition, glycosphingolipids, transforming growth factor-β
- 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
- PubMed
- 36504224 Full text @ EMBO J.
Citation
Zhang, J., van der Zon, G., Ma, J., Mei, H., Cabukusta, B., Agaser, C.C., Madunić, K., Wuhrer, M., Zhang, T., Ten Dijke, P. (2022) ST3GAL5-catalyzed gangliosides inhibit TGF-β-induced epithelial-mesenchymal transition via TβRI degradation. The EMBO journal. 42(2):e110553.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping