Abstract
Simple SummaryThe glycosyltransferase β1,4-N-acetylgalactosaminyltransferae 2 (B4GALNT2), product of the B4GALNT2 gene is responsible for the biosynthesis of the carbohydrate antigen Sda. 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 Lewisa and sialyl Lewisx antigens are associated with malignancy. Their biosynthesis and that of Sda 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 sLea/sLex inhibition. Thus, B4GALNT2 is a marker of better prognosis and a cancer-restraining enzyme in colorectal cancer, with a therapeutic potential. Terminal carbohydrate structures are particularly relevant in oncology because they can serve as cancer markers and alter the phenotype of cancer cells. The Sda antigen and the sialyl Lewisx and sialyl Lewisa (sLex and sLea) antigens are terminal structures whose biosynthesis is mutually exclusive. In this review, we describe the main features of the Sda antigen in cancer and its relationship with sLex/a antigens. Information was obtained from an extensive literature search and from The Cancer Genome Atlas (TCGA) public database. The Sda 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 sLea/sLex and reduced malignancy and stemness in cells constitutively expressing sLex/a antigens. However, consistent effects were observed upon B4GALNT2 forced expression and in cells not expressing sLex/a antigens. Thus, B4GALNT2 and the Sda antigen exert a tumor-restraining activity in CRC and probably other gastrointestinal cancers, independently of sLex/a antigens.
Highlights
The impact of glycosylation on cell behavior largely depends on the terminal portions of glycoconjugates
We have previously proposed that the right question to answer is not “why is sialyl Lewisx (sLex) high in colon cancer?” but rather: “why is sLex low in normal colon?” The reduced B4GALNT2 expression in CRC is part of the answer
Biglycan, overexpressed in CRC, is a good ligand for Toll-like receptor 4 (TLR4) [73,74]. This leads to the activation in CRC of the TLR4/NFkB inflammatory pathway, resulting in the previously mentioned epigenetic silencing of the SLC26A2 and ST6GALNA6 genes, responsible for sialyl 6-sulfo Lex and di-sialyl Lewisa biosynthesis [79,80]
Summary
The impact of glycosylation on cell behavior largely depends on the terminal portions of glycoconjugates. Examples of terminal structures include α2,3- and α2,6-linked sialic acids, polysialic acid, the AB0 blood group, and other fucosylated structures such as the sialyl Lewisx (sLex) and the sialyl Lewisa (sLea) antigens [1,2,3]. The Sda antigen is a terminal carbohydrate structure expressed on erythrocytes, in secretions [4], and in a few organs [5] by the vast majority of Caucasians. The Sda antigen was discovered independently by two groups in 1967 [6,7] and found to be inherited as a dominant character. Tfahcet,dwepheilnedtehneceenozfySmdae/Ba4cGtivAiLtyNTof boonthceSlldda i[f3fe5r]eanntidatBio4nGwALaNs uTn2c[l3e3a]r.wInasfahcitg, hwehr iilne tthhee epnozoyrmlyedaicfftievrietnytioaftebdotcheSlldsao[f35th] eancdolBo4nGicAcLrNypTt2, [B343G] wALasNhTi2gheexrpirnestshieonpoinocrrlyeadsiefdferuepnotinadtiefdfecreenlltsiaotfiothneocfotlhoenihcucmryapnt,cBo4loGnAcLaNnTce2reCxapcroe2sscioelnlsin[3c6re].ased upon differentiation of the human colon cancer Caco cells [36]
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