Transforming growth factor-beta challenge alters the N-, O-, and glycosphingolipid glycomes in PaTu-S pancreatic adenocarcinoma cells

Zhang, J.; Zhang, Z.J.; Holst, S.; Bloechl, C.; Madunic, K.; Wuhrer, M.; ... ; Zhang, T. (2022)

Article / Letter to editor

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and high mortality. Transforming growth factor-beta (TGF-beta) plays a key role in PDAC tumor progression, which is often associated with aberrant glycosylation. However, how PDAC cells respond to TGF-beta and the role of glycosylation therein is not well known. Here, we investigated the TGF-beta-mediated response and glycosylation changes in the PaTu-8955S (PaTu-S) cell line deficient in SMA-related and MAD-related protein 4 (SMAD4), a signal transducer of the TGF-beta signaling. PaTu-S cells responded to TGF-beta by upregulating SMAD2 phosphorylation and target gene expression. We found that TGF-beta induced expression of the mesenchymal marker N-cadherin but did not significantly affect epithelial marker E-cadherin expression. We also examined differences in N-glycans, O-glycans, and glycosphingolipid-linked glycans in PaTu-S cells upon TGF-beta stimulation. TGF-beta treatment primarily induced N-glycome aberrations involving elevated levels of branching, core fucosylation, and sialylation in PaTu-S cells, in agreement with TGF-beta-induced changes in the expression of glycosylation-associated genes. In addition, we observed differences in O glycosylation and glycosphingolipid glycosylation profiles after TGF-beta treatment, including lower levels of sialylated Tn antigen and neoexpression of globosides. Furthermore, the expression of transcription factor sex-determining region Y-related high-mobility group box 4 was upregulated upon TGF-beta stimulation, and its depletion blocked TGF-beta-induced N-glycomic changes. Thus, TGF-beta-induced N-glycosylation changes can occur in a sex-determining region Y-related high-mobility group box 4-dependent and SMAD4-independent manner in the pancreatic PaTu-S cancer cell line. Our results open up avenues to study the relevance of glycosylation in TGF-beta signaling in SMAD4-inactivated PDAC.

• All authors: Zhang, J.; Zhang, Z.J.; Holst, S.; Bloechl, C.; Madunic, K.; Wuhrer, M.; Dijke, P. ten; Zhang, T.
• Date: 2022-03-01
• Journal: Journal of Biological Chemistry
• Volume: 298
• Issue: 3
• DOI: doi:10.1016/j.jbc.2022.101717
• Link: https://www.sciencedirect.com/science/article/pii/S0021925822001570?via%...