B4GALT1-dependent galectin-8 binding with TGF-β receptor suppresses colorectal cancer progression and metastasis

Area of Science:

• Molecular biology
• Cancer research
• Glycobiology

Background:

• Transforming growth factor (TGF)-β signaling is crucial for epithelial-mesenchymal transition (EMT) and colorectal cancer (CRC) metastasis.
• Smad-dependent TGF-β signaling is disrupted in CRC cells, yet TGF-β receptors remain expressed.

Purpose of the Study:

• To investigate how tumor-associated N-glycosylation and a glycan-binding protein modulate TGF-β-driven CRC signaling and metastasis.
• To explore the role of galectin-8 in CRC progression.

Main Methods:

• Investigated galectin-8 interaction with TGF-β receptor type II.
• Assessed the impact of galectin-8 depletion and recombinant treatment on CRC cell migration and signaling pathways (RAS, Src, JNK).
• Examined the role of β4-galactosyltransferase-I (B4GALT1) in galectin-8's anti-migratory effect.
• Utilized an intra-splenic injection model to evaluate galectin-8's effect on tumor development and metastasis in vivo.

Main Results:

• Galectin-8 inhibited TGF-β-induced EMT by competing with TGF-β binding to the TGF-β receptor.
• Galectin-8 depletion enhanced CRC cell migration via increased TGF-β-receptor-mediated RAS and Src signaling.
• Recombinant galectin-8 treatment attenuated migration, induced JNK-dependent apoptosis, and suppressed tumor development and metastasis.
• Galectin-8's anti-migratory effect was dependent on B4GALT1, an enzyme involved in N-glycan synthesis, which showed increased expression in clinical CRC samples.

Conclusions:

• Galectin-8 alters non-canonical TGF-β responses in CRC cells.
• Galectin-8 suppresses CRC progression and metastasis by modulating TGF-β signaling and inducing apoptosis.
• Targeting galectin-8 and its interaction with N-glycosylation pathways presents a potential therapeutic strategy for colorectal cancer.