期刊
EMBO JOURNAL
卷 42, 期 2, 页码 -出版社
WILEY
DOI: 10.15252/embj.2021110553
关键词
epithelial-mesenchymal transition; glycosphingolipids; ST3GAL5; transforming growth factor-beta; UDP-glucose ceramide glucosyltransferase
Epithelial-mesenchymal transition (EMT) is important in cancer cell metastasis. The abundance of glycosphingolipids (GSLs), specifically ganglioside subtypes, decreases during TGF-beta-induced EMT. Inhibition of UDP-glucose ceramide glucosyltransferase (UGCG), the enzyme responsible for GSL biosynthesis, promotes TGF-beta signaling and EMT. ST3GAL5-synthesized a-series gangliosides inhibit TGF-beta signaling and EMT in lung cancer cells.
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.
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