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

Autor: Zhang J; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands., van der Zon G; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands., Ma J; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands., Mei H; Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands., Cabukusta B; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands., Agaser CC; Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands., Madunić K; Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands., Wuhrer M; Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands., Zhang T; Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands., Ten Dijke P; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2023 Jan 16; Vol. 42 (2), pp. e110553. Date of Electronic Publication: 2022 Dec 12.
DOI: 10.15252/embj.2021110553
Abstrakt: 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.
(© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
Databáze: MEDLINE
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