HS2ST1-dependent signaling pathways determine breast cancer cell viability, matrix interactions and invasive behavior.
Fiche publication
Date publication
juin 2020
Journal
Cancer science
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BREZILLON Stéphane, Pr SOCKALINGUM Ganesh
Tous les auteurs :
Vijaya Kumar A, Brézillon S, Untereiner V, Dhruvananda Sockalingum G, Kumar Katakam S, Taha Mohamed H, Kemper B, Greve B, Mohr B, Ibrahim SA, Goycoolea FM, Kiesel L, Pavão MSG, Motta JM, Götte M
Lien Pubmed
Résumé
Heparan sulfate proteoglycans (HSPGs) act as signaling coreceptors by interactions 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 to control cells. HS2ST1 overexpressing cells showed reduced MAPK signaling responses to FGF-2, and altered expression of 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.
Mots clés
2-O sulfotransferase, MAPK signaling pathway, breast cancer, heparan sulfate, proteoglycan
Référence
Cancer Sci.. 2020 Jun 23;: