ST3GAL5-catalyzed gangliosides inhibit TGF-ß-induced epithelial-mesenchymal transition via TßRI degradation.
EMBO J
; 42(2): e110553, 2023 01 16.
Article
em En
| MEDLINE
| ID: mdl-36504224
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-ß-induced EMT in NMuMG mouse mammary epithelial cells and A549 human lung adenocarcinoma cells. Transcriptional profiling showed that TGF-ß/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-ß signaling and TGF-ß-induced EMT. UGCG inhibition promoted A549 cell migration, extravasation in the zebrafish xenograft model, and metastasis in mice. Mechanistically, GSLs inhibited TGF-ß signaling by promoting lipid raft localization of the TGF-ß type I receptor (TßRI) and by increasing TßRI ubiquitination and degradation. Importantly, we identified ST3GAL5-synthesized a-series gangliosides as the main GSL subtype involved in inhibition of TGF-ß signaling and TGF-ß-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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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Transformador beta
/
Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
EMBO J
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Holanda