The Critical Role of GALNTs‐Regulated O‐GalNAc Glycosylation in Cancer Malignancy

Aberrant mucin-type O-glycosylation, mediated by the Polypeptide N-acetylgalactosaminyltransferase (GALNT) family of enzymes, is a defining feature of many cancers and has also been strongly linked to non-neoplastic conditions, including developmental disorders and metabolic abnormalities. Mucin-type O-GalNAc glycosylation, a prevalent and highly specific form of post-translational modification, is centrally involved in key processes underlying cancer progression, such as cell signaling, invasion, angiogenesis, and metastasis. It is intricately linked to a diverse array of human diseases, with a particular association with cancer. Ongoing research endeavors to elucidate the functional mechanisms by which GALNT enzymes regulate O-GalNAc glycosylation, thereby enhancing our understanding of their pivotal roles in cancer biology. Although significant advances have been made in understanding their contributions to cancer initiation and progression, a comprehensive characterization of both the GALNT family and O-GalNAc glycosylation in oncology remains lacking. This review aims to summarize the structure of the GALNT family and its regulatory roles in the initiation and elongation of O-GalNAc glycans, providing an in-depth exploration of the functions of GALNT-mediated O-GalNAc glycosylation in cancer. Ultimately, these insights will help uncover underlying oncogenic mechanisms and may offer new potential directions for the development of anticancer therapeutics and diagnostic biomarkers.