title: β-Galactoside α2,6-sialyltranferase 1 promotes transforming growth factor-β-mediated epithelial-mesenchymal transition.
abstract: β-Galactoside α2,6-sialyltranferase 1 (ST6GAL1) catalyzes the addition of terminal α2,6-sialylation to N-glycans. Increased expression of ST6GAL1 has been reported in diverse carcinomas and highly correlates with tumor progression. Here, we report that St6gal1 transcription and α2,6-sialylated N-glycans are up-regulated during TGF-β-induced epithelial-mesenchymal transition (EMT) in GE11 cells, requiring the Sp1 element within the St6gal1 promoter. Knockdown of St6gal1 strongly suppressed TGF-β-induced EMT with a concomitant increase in E-cadherin expression, a major determinant of epithelial cell adherens junctions. Conversely, overexpression of ST6GAL1 increased the turnover of cell surface E-cadherin and promoted TGF-β-induced EMT. Overexpressing β-galactoside α2,3-sialyltranferase 4 had little influence on EMT, indicating specificity for α2,6-sialylation. The basal mesenchymal phenotype of MDA-MB-231 human breast cancer cells was partially reversed by ST6GAL1 silencing. Moreover, ST6GAL1 knockdown inhibited the phosphorylation of Akt, but not Smad2, suggesting that ST6GAL1 contributes to EMT through a non-Smad signaling pathway. Taken together, our data indicate that ST6GAL1 promotes TGF-β-dependent EMT as well as maintenance of the mesenchymal state by growth signaling, providing a plausible mechanism whereby up-regulated ST6GAL1 may promote malignant progression.
authors.affiliation: From the Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aobaku, Sendai, Miyagi, 981-8558, Japan and.
authors.forename: Jishun
authors.initials: J
authors.lastname: Lu
authors.affiliation: From the Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aobaku, Sendai, Miyagi, 981-8558, Japan and.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Isaji
authors.affiliation: From the Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aobaku, Sendai, Miyagi, 981-8558, Japan and.
authors.forename: Sanghun
authors.initials: S
authors.lastname: Im
authors.affiliation: From the Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aobaku, Sendai, Miyagi, 981-8558, Japan and.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: the National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo, 158-8501, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Hashii
authors.affiliation: the National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo, 158-8501, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takakura
authors.affiliation: the National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo, 158-8501, Japan.
authors.forename: Nana
authors.initials: N
authors.lastname: Kawasaki
authors.affiliation: From the Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aobaku, Sendai, Miyagi, 981-8558, Japan and jgu@tohoku-pharm.ac.jp.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Gu
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D012799:Sialyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D012799:Sialyltransferases; D016329:Sp1 Transcription Factor; D016212:Transforming Growth Factor beta; C093493:ST6GAL1 protein, human; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
keywords: Cadherin; Cell Migration; Epithelial-Mesenchymal Transition (EMT); N-Linked Glycosylation; Sialyltransferase