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

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.

High expression of embryonic stem cell marker SSEA3 confers poor prognosis and promotes epithelial mesenchymal transition in hepatocellular carcinoma

“…But, the effects of the inhibitor was abrogated by the addition of GM2 or Cg4 [ 32 ]. ST3GAL5 and its downstream gangliosides were involved in the inhibition TGF-β-induced EMT in A549 [ 33 ]. Deletion of ST8SIA1 in ovarian cancer cells induced epithelial cell features, whereas loss of globosides in ΔA4GALT cells, resulted in EMT [ 34 , 35 ].…”

Identify Candidate Genes Associated with the Weight and Egg Quality Traits in Wenshui Green Shell-Laying Chickens by the Copy Number Variation-Based Genome-Wide Association Study

“…The ST3GAL5 gene is a protein-coding gene that plays a crucial role in glycosylation reactions and is involved in biological processes such as immune regulation and neural system development [ 56 , 57 ]. Research conducted in chickens has found that the ST3GAL5 gene exhibited activity toward lactosylceramide.…”

N-Glycosylation of LRP6 by B3GnT2 Promotes Wnt/β-Catenin Signalling

“…The distribution of LRP6 in different cellular compartments plays a crucial role in its activity: for example, it has been reported that lipid-raft-located LRP6 forms a complex with Wnt and Frizzled proteins and undergoes caveolin-mediated endocytosis to activate Wnt/β-catenin signalling, while LRP6 in nonlipid rafts is internalised with clathrin to inhibit Wnt/β-catenin signalling [ 66 , 67 ]. A recent study has also demonstrated a role for glycosphingolipids in the localisation and internalisation of TGFβR1 receptors within lipid raft domains [ 68 ]. In addition to the effect B3GnT2 may have on LRP6 interactions, it will therefore also be important to investigate whether B3GnT2 can regulate the redistribution of LRP6 in different cellular compartments.…”