Abstract
Sialyl Lewis antigens are selectin ligands involved in leukocyte trafficking and cancer metastasis. Biosynthesis of these selectin ligands occurs by the sequential actions of several glycosyltransferases in the Golgi apparatus following synthesis of the protein backbone in the endoplasmic reticulum. In this study, we examine how the synthesis of sialyl Lewis a (sLea) is regulated in prostatic cells and identify a mucin that carries this glycotope. We treat human prostatic cells including one normal and three cancerous cells with histone deacetylase inhibitors, valproic acid, tricostatin A (TSA), and suberoylanilide hydroxamic acid (SAHA), and then monitor the expression of sLea. We have found that SAHA enhances the production of sLea in normal prostatic RWPE-1 cells but not prostatic cancer cells. Employing siRNA technology and co-immunoprecipitation, we show that the sLea is associated with MUC1, which is confirmed by confocal immunofluorescence microscopy and proximity ligation assay. The SAHA-induced production of sLea in RWPE-1 cells is resulted from upregulation of B3GALT1 gene via enhancement of acetylated histone-3 and histone-4. Interestingly, PC3 and LNCaP C-81 cells do not produce detectable amounts of sLea despite expressing high levels of B3GALT1. However, the MUC1-associated sLea is generated in these cells after introduction of MUC1 cDNA. We conclude that the synthesis of sLea is controlled by not only peptide backbone of the glycoprotein but also glycoprotein-specific glycosyltransferases involved in the synthesis of sLea. Further, the SAHA induction of this selectin ligand in normal prostatic cells may pose a potentially serious side effect of this drug recently approved by the US Food and Drug Administration.
Highlights
IntroductionThe tumor invasion and metastasis properties acquired during cancer progression include increased invasion of surrounding tissues, escape from primary site, and establishment of tumors at distant sites
Tumor metastasis is the primary cause of the mortality of cancer patients
We found that MUC1 co-localized with sialyl Lewis a (sLea) induced by suberoylanilide hydroxamic acid (SAHA) at the plasma membrane of RWPE-1 cells (Fig. 4A), validating the observation that MUC1 is the carrier of sLea
Summary
The tumor invasion and metastasis properties acquired during cancer progression include increased invasion of surrounding tissues, escape from primary site, and establishment of tumors at distant sites This process is driven by different families of adhesion molecules including integrins, members of the immunoglobulin superfamily, selectins and carbohydrate ligands, such as sialyl Lewis x (sLex) and sialyl Lewis a (sLea) [1]. SLea is a ligand for endothelial leukocyte adhesion molecule and is associated with metastasis [9,10,11] of human colon cancer [12,13] and pancreatic adenocarcinoma [14] Both sialyl Lewis antigens are found on various glycoproteins and mucins, including MUC1, which serve as selectin ligands to mediate leukocyte adhesion and hematogenous metastasis of cancer cells [15,16,17]. The type-1 backbone structure is synthesized by b1,3-galactosyltransferases (B3GALTs) while type-2 by b1,4-galactosyltransferases (B4GALTs)
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