UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase-6 (pp-GalNAc-T6): Role in cancer and prospects as a drug target

UDP-N-acetyl-d-galactosamine: polypeptide N-acetylgalactosaminyl transferase-6 (pp-GalNAc-T6) is a member of the N-acetyl-d-galactosamine transferase family. It catalyzes the addition of N-acetyl-d-galactosamine to proteins, often the first step in O-glycosylation of proteins. Glycosylated proteins play important roles in vivo in the cell membrane. These are often involved in cell-cell adhesion, cytoskeleton regulation and immune recognition. pp-GalNAc-T6 has been shown to be upregulated in a number of types of cancer. Abnormally glycosylated forms of mucin 1 (substrate of the enzyme), are used clinically as a biomarker for breast cancer. There is potential for other products of the pp-GalNAc-T6 catalyzed reaction to be used. It is also possible that pp-GalNAc-T6 itself could be used as a biomarker, since levels of this protein tend to be low in non-malignant tissues. pp-GalNAc-T6 has been implicated in malignant transformation and metastasis of cancer cells. As such, it has considerable potential as a target for chemotherapy. To date, no selective inhibitors of the enzyme have been identified. However, general inhibitors of the enzyme family result in reduced cell surface O-linked glycosylation and induce apoptosis in cultured cells. Thus, a selective inhibitor of pp-GalNAc-T6 is likely to target cancer cells and could be developed into a novel anticancer therapy.