Epigenetic Regulation of Galectin-3 Expression by β1 Integrins Promotes Cell Adhesion and Migration

• Published in: The Journal of biological chemistry 2012-12, Vol.287 (53), p.44684-44693
• Main Authors: Margadant, Coert, van den Bout, Iman, van Boxtel, Antonius L., Thijssen, Victor L., Sonnenberg, Arnoud
• Format: Article
• Language: English
• Subjects: Animals; Cell Adhesion; Cell Biology; Cell Line; Cell Migration; Cell Movement; DNA Methylation; EMT; Epigenesis, Genetic; Galectin; Galectin 3 - genetics; Galectin 3 - metabolism; Gene Expression Regulation; Humans; Integrin; Integrin beta1 - genetics; Integrin beta1 - metabolism; Integrin beta3 - genetics; Integrin beta3 - metabolism; Methylation; Mice; Mice, Knockout; Up-Regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.426445

Introduction of the integrin β1- but not the β3-subunit in GE11 cells induces an epithelial-to-mesenchymal-transition (EMT)-like phenomenon that is characterized by the loss of cell-cell contacts, cell scattering, increased cell migration and RhoA activity, and fibronectin fibrillogenesis. Because galactose-binding lectins (galectins) have been implicated in these phenomena, we investigated whether galectins are involved in the β1-induced phenotype. We examined 9 galectins and, intriguingly, found that the expression of galectin-3 (Gal-3) is specifically induced by β1 but not by β3. Using β1-β3 chimeric integrins, we show that the induction of Gal-3 expression requires the hypervariable region in the extracellular domain of β1, but not its cytoplasmic tail. Furthermore, Gal-3 expression does not depend on RhoA signaling, serum factors, or any of the major signal transduction pathways involving protein kinase C (PKC), p38 mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated kinase-1/-2 (ERK-1/2), phosphatidylinositol-3-OH kinase (PI3-K), or Src kinases. Instead, Gal-3 expression is controlled in an epigenetic manner. Whereas DNA methylation of the Lgals3 promoter maintains Gal-3 silencing in GE11 cells, expression of β1 causes its demethylation, leading to transcriptional activation of the Lgals3 gene. In turn, Gal-3 expression enhances β1 integrin-mediated cell adhesion to fibronectin (FN) and laminin (LN), as well as cell migration. Gal-3 also promotes β1-mediated cell adhesion to LN and Collagen-1 (Col)-1 in cells that endogenously express Gal-3 and β1 integrins. In conclusion, we identify a functional feedback-loop between β1 integrins and Gal-3 that involves the epigenetic induction of Gal-3 expression during integrin-induced EMT and cell scattering. β1 integrins induce EMT-like phenomena. β1 integrins epigenetically regulate the expression of galectin-3, which in turn enhances β1-mediated cell adhesion and migration. A functional feedback-loop exists between β1 integrins and galectin-3, to enhance integrin function. There is cross-talk between integrins and galectins at multiple levels, regulating events important for cancer biology.