ST3GAL5-catalyzed gangliosides inhibit TGF-beta-induced epithelial-mesenchymal transition via T beta RI degradation

Zhang, J.; Zon, G. van der; Ma, J.; Mei, H.L.; Cabukusta, B.; Agaser, C.C.; ... ; Dijke, P. ten (2022)

Article / Letter to editor

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-beta-induced EMT in NMuMG mouse mammary epithelial cells and A549 human lung adenocarcinoma cells. Transcriptional profiling showed that TGF-beta/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-beta signaling and TGF-beta-induced EMT. UGCG inhibition promoted A549 cell migration, extravasation in the zebrafish xenograft model, and metastasis in mice. Mechanistically, GSLs inhibited TGF-beta signaling by promoting lipid raft localization of the TGF-beta type I receptor (T beta RI) and by increasing T beta RI ubiquitination and degradation. Importantly, we identified ST3GAL5-synthesized a-series gangliosides as the main GSL subtype involved in inhibition of TGF-beta signaling and TGF-beta-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.

• epithelial-mesenchymal transition
• glycosphingolipids
• ST3GAL5
• transforming growth factor-beta
• UDP-glucose ceramide glucosyltransferase

• All authors: Zhang, J.; Zon, G. van der; Ma, J.; Mei, H.L.; Cabukusta, B.; Agaser, C.C.; Madunic, K.; Wuhrer, M.; Zhang, T.; Dijke, P. ten
• Date: 2022-12-12
• Journal: The EMBO Journal
• Volume: 42
• DOI: doi:10.15252/embj.2021110553
• Link: https://www.embopress.org/doi/full/10.15252/embj.2021110553