GALNTs: master regulators of metastasis-associated epithelial-mesenchymal transition (EMT)?

Abstract

In humans, the UDP-N-α-D galactosamine:polypeptide N-acetylgalactosaminyltransferases family (ppGalNAc-Ts, GalNAc-Ts or GALNTs) comprises 20 isoenzymes. They are responsible for the initial synthesis of α-GalNAc1,3-O-Ser/Thr, or Tn antigen, at initiation of mucin type O-linked glycosylation. This structure is normally extended by the further sequential action of glycosytransferases to build more complex linear or branched O-linked structures, but in cancers it is frequently left unelaborated, and its presence is often associated with poor patient prognosis. Altered levels of GALNT expression or distribution have also been extensively reported in a wide range of cancers. These changes would be predicted to result in marked alterations in GalNAc O-linked glycosylation, including altered levels of site specific O-linked glycosylation and changes in the glycan structures formed, including, potentially, exposure of truncated O-glycans such as Tn antigen. Many reports have demonstrated that altered levels of specific GALNTs have prognostic significance in cancers, or shown that they are associated with changes in cell behaviour, including proliferation, migration, invasion or growth and metastasis in animal models. We have previously reviewed how deregulation of GALNTs in several epithelial cancers is a feature of different stages metastasis. Here we consider evidence that changes in GALNT expression, and therefore consequent alterations in GalNAc O-linked glycosylation, may directly influence molecules implicated in aspects of epithelial-mesenchymal transition (EMT), a fundamental aspect of cancer metastasis, during which epithelial cancer cells lose their cell-cell junctions, apical-basal polarity and adhesive interactions with basement membrane and become mesenchymal, with a spindle-shaped morphology and increased migratory capacity.

Keywords: Epithelial-mesenchymal transition (EMT); GalNAc O-glycosylation; Metastasis; Tn antigen; UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferases (GALNTs).