HS2ST1-dependent signaling pathways determine breast cancer cell viability, matrix interactions, and invasive behavior

Heparan sulfate proteoglycans (HSPGs) act as signaling co-receptors by interaction of their sulfated glycosaminoglycan chains with numerous signaling molecules. In breast cancer, the function of heparan sulfate 2-O-sulfotransferase (HS2ST1), the enzyme mediating 2-O-sulfation of HS, is largely unkno...

Authors: Kumar, Archana Vijaya
Brézillon, Stéphane
Untereiner, Valérie
Sockalingum, Ganesh Dhruvananda
Katakam, Sampath Kumar
Mohamed, Hossam Taha
Kemper, Björn
Greve, Burkhard
Mohr, Benedikt
Ibrahim, Sherif
Goycoolea, Francisco Martin
Kiesel, Ludwig
Pavão, Mauro S. G.
Motta, Juliana M.
Götte, Martin
Division/Institute:FB 13: Biologie
Document types:Article
Media types:Text
Publication date:2020
Date of publication on miami:29.06.2022
Modification date:18.07.2022
Edition statement:[Electronic ed.]
Source:Cancer Science 111 (2020) 8, 2907-2922
Subjects:2-O-sulfotransferase; breast cancer; heparan sulfate; MAPK signaling pathway; proteoglycan
DDC Subject:610: Medizin und Gesundheit
License:CC BY-NC-ND 4.0
Language:English
Funding:Finanziert über die DEAL-Vereinbarung mit Wiley 2019-2022.
Format:PDF document
URN:urn:nbn:de:hbz:6-63059650863
Other Identifiers:DOI: 10.17879/43069483491
Permalink:https://nbn-resolving.de/urn:nbn:de:hbz:6-63059650863
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  • Digital documents:10.1111_cas.14539.pdf

    Heparan sulfate proteoglycans (HSPGs) act as signaling co-receptors by interaction of their sulfated glycosaminoglycan chains with numerous signaling molecules. In breast cancer, the function of heparan sulfate 2-O-sulfotransferase (HS2ST1), the enzyme mediating 2-O-sulfation of HS, is largely unknown. Hence, a comparative study on the functional consequences of HS2ST1 overexpression and siRNA knockdown was performed in the breast cancer cell lines MCF-7 and MDA-MB-231. HS2ST1 overexpression inhibited Matrigel invasion, while its knockdown reversed the phenotype. Likewise, cell motility and adhesion to fibronectin and laminin were affected by altered HS2ST1 expression. Phosphokinase array screening revealed a general decrease in signaling via multiple pathways. Fluorescent ligand binding studies revealed altered binding of fibroblast growth factor 2 (FGF-2) to HS2ST1-expressing cells compared with control cells. HS2ST1-overexpressing cells showed reduced MAPK signaling responses to FGF-2, and altered expression of epidermal growth factor receptor (EGFR), E-cadherin, Wnt-7a, and Tcf4. The increased viability of HS2ST1-depleted cells was reduced to control levels by pharmacological MAPK pathway inhibition. Moreover, MAPK inhibitors generated a phenocopy of the HS2ST1-dependent delay in scratch wound repair. In conclusion, HS2ST1 modulation of breast cancer cell invasiveness is a compound effect of altered E-cadherin and EGFR expression, leading to altered signaling via MAPK and additional pathways.