The Cancer-Associated Antigens Sialyl Lewis(a/x) and Sd(a): Two Opposite Faces of Terminal Glycosylation

SIMPLE SUMMARY: The glycosyltransferase β1,4-N-acetylgalactosaminyltransferae 2 (B4GALNT2), product of the B4GALNT2 gene is responsible for the biosynthesis of the carbohydrate antigen Sd(a). Both the enzyme and its cognate antigen display a restricted pattern of tissue expression and modulation in colorectal, gastric, and mammary cancers. In colorectal cancer, B4GALNT2 is generally downregulated, but patients displaying higher expression survive longer. The sialyl Lewis(a) and sialyl Lewis(x) antigens are associated with malignancy. Their biosynthesis and that of Sd(a) are mutually exclusive. Forced expression of B4GALNT2 in colorectal cancer cell lines modulates the transcriptome towards lower malignancy, reducing stemness. These effects are independent of B4GALNT2-induced sLe(a)/sLe(x) inhibition. Thus, B4GALNT2 is a marker of better prognosis and a cancer-restraining enzyme in colorectal cancer, with a therapeutic potential. ABSTRACT: Terminal carbohydrate structures are particularly relevant in oncology because they can serve as cancer markers and alter the phenotype of cancer cells. The Sd(a) antigen and the sialyl Lewis(x) and sialyl Lewis(a) (sLe(x) and sLe(a)) antigens are terminal structures whose biosynthesis is mutually exclusive. In this review, we describe the main features of the Sd(a) antigen in cancer and its relationship with sLe(x/a) antigens. Information was obtained from an extensive literature search and from The Cancer Genome Atlas (TCGA) public database. The Sd(a) biosynthetic enzyme B4GALNT2 undergoes downregulation in colorectal (CRC) and stomach cancer, while it is ectopically expressed by a minority of breast cancer (BRCA) patients. High expression of B4GALNT2 is associated with better prognosis and a less malignant gene expression profile in CRC, while the opposite occurs in BRCA. The regulation of B4GALNT2 expression in CRC is multifactorial, involving gene methylation and miRNA expression. Forced expression of B4GALNT2 inhibited sLe(a)/sLe(x) and reduced malignancy and stemness in cells constitutively expressing sLe(x/a) antigens. However, consistent effects were observed upon B4GALNT2 forced expression and in cells not expressing sLe(x/a) antigens. Thus, B4GALNT2 and the Sd(a) antigen exert a tumor-restraining activity in CRC and probably other gastrointestinal cancers, independently of sLe(x/a) antigens.