The Sd(a) Synthase B4GALNT2 Reduces Malignancy and Stemness in Colon Cancer Cell Lines Independently of Sialyl Lewis X Inhibition

Background: The Sd(a) antigen and its biosynthetic enzyme B4GALNT2 are highly expressed in healthy colon but undergo a variable down-regulation in colon cancer. The biosynthesis of the malignancy-associated sialyl Lewis x (sLe(x)) antigen in normal and cancerous colon is mediated by fucosyltransferase 6 (FUT6) and is mutually exclusive from that of Sd(a). It is thought that the reduced malignancy associated with high B4GALNT2 was due to sLe(x) inhibition. Methods: We transfected the cell lines SW480 and SW620, derived respectively from a primary tumor and a metastasis of the same patient, with the cDNAs of FUT6 or B4GALNT2, generating cell variants expressing either the sLe(x) or the Sd(a) antigens. Transfectants were analyzed for growth in poor adherence, wound healing, stemness and gene expression profile. Results: B4GALNT2/Sd(a) expression down-regulated all malignancy-associated phenotypes in SW620 but only those associated with stemness in SW480. FUT6/sLe(x) enhanced some malignancy-associated phenotypes in SW620, but had little effect in SW480. The impact on the transcriptome was stronger for FUT6 than for B4GALNT2 and only partially overlapping between SW480 and SW620. Conclusions: B4GALNT2/Sd(a) inhibits the stemness-associated malignant phenotype, independently of sLe(x) inhibition. The impact of glycosyltransferases on the phenotype and the transcriptome is highly cell-line specific.