GALNT6 is highly expressed in many types of cancer, but expression of GALNT6 is hardly detectable in human normal tissues (Park et al., 2010).

Human GALNT6 gene is located on 12 chromosome at q13.13 location. The GALNT6 gene is composed of 12 exons and ORF (open reading frame) is 1869 bp.

Human GALNT6 gene encodes 622 amino acids of 71159 Da. The protein is involved in the first step of O-type glycosylation by transferring UDP-GalNAc to Ser/Thr site of substrate protein. GALNT6 was firstly identified as a glycosyltransferase with high sequence similarity to GALNT3 (Bennett et al., 1999). GALNT6 has similar kinetic properties with other GALNTs but preferentially glycosylated fibronectin peptide in vitro. Because of expression in WI38 fibroblast cells, GALNT6 was regarded as a candidate for synthesis of the oncofetal fibronectin (Bennett et al., 1999). GALNT6 has two possible N-type glycosylation sites at N476 and N611.

The mucin-type O-glycosylation is initiated by GALNT family members that transfer N-acetyl-alpha-D-galactosamine (GalNAc) to serine or threonine residues on the target protein (Ten Hagen et al., 2003). This modification occurs in the Golgi complex and is presumably controlled by the expressions and distributions of GALNT proteins (Brooks et al., 2007). Interestingly, structural alterations of these glycan chains are often detected in cancer cells, especially in breast cancer. For instances, the O-glycans were often truncated (core 1-based type) in breast carcinoma cells, whereas they were extended its chain (core 2-based type) in normal breast cells (Burchell et al., 2001). O-type glycosylation is one of common modifications that have multiple functions related to the folding, stability, and targeting of various glycoproteins (Carraway et al., 2007). Accumulating evidences have suggested that the GALNT family members are involved in several cellular functions by catalyzing substrates specific to each member. For instances, glycosylation by GALNT3 prevents proteolytic processing of FGF23 (fibroblast growth factor 23) and that by GALNT14 promotes ligand-stimulated clustering of death receptors (Wagner et al., 2007; Ichikawa et al., 2009).

GALNT6 is highly expressed in many types of cancer including breast, gastric, kidney, oral, and pancreatic cancer (Berois et al., 2006; Gomes et al., 2009; Kitada et al., 2013; Wandall et al., 2007; Li et al., 2011). However, in human normal tissues, GALNT6 is merely expressed in normal tissues and vital organs including lung, heart, liver, and kidney (Park et al., 2010). A specific expression of GALNT6 was also reported in the nonkeratinized epithelium of ocular cicatricial pemphigoid (OCP) patients (Argüeso et al., 2003).

Similarly to other isoforms in the GALNT family, GALNT6 is localized in the Golgi complex as shown by double immunofluorescence staining with anti-GALNT6 mAb and anti-Golgi-58k mAb (Park et al., 2010).

GALNT6 is involved in the first step of O-type glycosylation, and thereby may influence on folding, stability, and subcellular localization of target proteins. GALNT6 was reported to stabilize MUC1 protein throughout O-glycosylation and subsequently the accumulated MUC1 protein promoted breast cancer cell proliferation and induced anti-adhesive effects (Park et al., 2010). By O-glycosylation of fibronectin protein, GALNT6 showed transformational potentials through disruptive acinar morphogenesis and cellular changes similar to EMT (epithelial-to-mesenchymal transition) in normal mammary epithelial cell (Park et al., 2011). The GALNT6-mediated O-glycosylation of fibronectin was also reported in the TGF-β-induced EMT process in human prostate cells (Freire-de-Lima et al., 2011).

GALNT6 has 30~63% of amino acid homology with other family members, with the highest homology to GALNT3 (63%). In crystal structure analysis of murine GALNT isoforms, GALNT1 was reported to be more similar to GALNT6 according to the electrostatic surface potential models (Fritz et al., 2004).