UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase- 6 (pp-GalNAc-T6): Role in Cancer and Prospects as a Drug Target

Abstract

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 Oglycosylation 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 nonmalignant 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 Olinked 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.

Early-Stage Loss of GALNT6 Predicts Poor Clinical Outcome in Colorectal Cancer

“…GalNAc-Ts are the largest glycosyltransferase enzyme family catalyzing a single known glycosidic linkage, and they have different but overlapping substrate specificities and patterns of expression (12)(13)(14)(15). In particular, N-acetylgalatosaminyltransferase 6 (GALNT6) has been found to be differentially expressed in various cancers (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). In colorectal cancer, GALNT6 is identified as one of the susceptibility genes (28), and GALNT6 expression is involved in oncogenic transformation and progression (29,30).…”

Perspective on Cancer Therapeutics Utilizing Analysis of Circulating Tumor Cells

“…The analysis of glycosylation of CTCs can be analyzed by carbohydrate microarrays and a high-speed fiber-optic array scanning technology. Arrays of glycans with micro arrays are used for the high throughput mapping of cell wall polysaccharide populations across a range of samples [ 43 , 44 ]. Using a carbohydrate microarray, the anti-tumor monoclonal antibody is tested against a large panel of carbohydrate antigens and a potential tumor glycan marker can discover in CTCs [ 43 ].…”

Tunable Approach to C-Linked Analogs of Glycosamines

“…2-Amino-2-deoxy-sugars and their N- and O -glycoconjugates are ubiquitous key biomolecules that are involved in numerous fundamental biological events . Typical examples contain d -glucosamine, − d -galactosamine, , d -allosamine, and d -mannosamine. , …”