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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.

The Cancer-Associated Antigens Sialyl Lewisa/x and Sda: Two Opposite Faces of Terminal Glycosylation