Histone deacetylase-mediated regulation of chondroitin 4-O-sulfotransferase-1 (Chst11) gene expression by Wnt/β-catenin signaling

Abstract Chondroitin sulfate (CS) proteoglycans are abundant extracellular and cell surface molecules that consist of a protein core to which highly sulfated CS chains are covalently attached. The CS backbone is composed of repeating disaccharide units [-GlcA-GalNAc-] n , and during synthesis the CS chains acquire structural variability due to the action of sulfotransferases. Specific sulfation patterns are recognized by a large variety of proteins, including growth factors, morphogens, and extracellular matrix proteins, and these interactions regulate key events in development and normal physiology. Therefore, it is important to understand how gene expression of CS sulfotransferases is regulated. We previously found that Wnt signaling regulates the sulfation patterns of cell-associated CS chains by suppressing expression of chondroitin 4-O-sulfotaransferase-1 ( C4ST-1 ), a CS biosynthetic enzyme. Here we investigated the mechanism underlying the regulation of C4ST-1 gene expression by Wnt/β-catenin signaling. Although C4ST-1 mRNA of 3′-UTR contains three binding sites for microRNAs (miRNA), these miRNAs played little role in controlling C4ST-1 gene expression. In contrast, the suppression of C4ST-1 gene expression by Wnt/β-catenin signaling can be recovered by treatment with trichostatin A, but not with 5′-aza-2′-deoxycytidine. These results suggest that the Wnt/β-catenin signal pathway controls C4ST-1 gene expression mainly through histone deacetylase.