Significant Roles of Notch O-Glycosylation in Cancer

Abstract

Notch signaling, which was initially identified in Drosophila wing morphogenesis, plays pivotal roles in cell development and differentiation. Optimal Notch pathway activity is essential for normal development and dysregulation of Notch signaling leads to various human diseases, including many types of cancers. In hematopoietic cancers, such as T-cell acute lymphoblastic leukemia, Notch plays an oncogenic role, while in acute myeloid leukemia, it has a tumor-suppressive role. In solid tumors, such as hepatocellular carcinoma and medulloblastoma, Notch may have either an oncogenic or tumor-suppressive role, depending on the context. Aberrant expression of Notch receptors or ligands can alter the ligand-dependent Notch signaling and changes in trafficking can lead to ligand-independent signaling. Defects in any of the two signaling pathways can lead to tumorigenesis and tumor progression. Strikingly, O-glycosylation is one such process that modulates ligand–receptor binding and trafficking. Three types of O-linked modifications on the extracellular epidermal growth factor-like (EGF) repeats of Notch receptors are observed, namely O-glucosylation, O-fucosylation, and O-N-acetylglucosamine (GlcNAc) modifications. In addition, O-GalNAc mucin-type O-glycosylation outside the EGF repeats also appears to occur in Notch receptors. In this review, we first briefly summarize the basics of Notch signaling, describe the latest information on O-glycosylation of Notch receptors classified on a structural basis, and finally describe the regulation of Notch signaling by O-glycosylation in cancer.

Cancer-associated Notch receptor variants lead to O-fucosylation defects that deregulate Notch signaling

“…As mentioned previously, alterations of glycosyltransferases associated with O- glycosylation of N1 have been reported in cancers ( 15 , 16 ). This is notably the case for POFUT1, where amplification, mutation, or upregulation has been found in hepatocellular carcinoma ( 35 ), colorectal cancer ( 36 , 37 ), glioblastoma ( 38 ), and squamous cell carcinoma ( 39 ).…”

“…Conversely, a gain of function (GOF) of N1 has been found in various lymphomas/leukemia ( 11 , 12 , 13 ) and breast cancer ( 14 ). Glycosylation of the Notch extracellular domain (NECD) regulates its activity and is essential for its function, and alterations in the glycosyltransferases modifying the NECD have been implicated in a number of cancers ( 15 , 16 ).…”

Targeting the Conformational Change in ArnA Dehydrogenase for Selective Inhibition of Polymyxin Resistance

“…Consequently, UDP-GlcA decarboxylase purifies with NAD + stoichiometrically bound . The same is true for the reactions catalyzed by three other human homologs of ArnA_DH: UDP-glucose epimerase (GALE), central to the Leloir pathway of galactose metabolism, protein glycosylation, and the synthesis of proteoglycans and glycolipids; , GDP-mannose 4,6-dehydratase in the pathway for biosynthesis of the essential sugar donor GDP-fucose, whose deficiency leads to blood disorders and significantly impacts cancer biology; − and dTDP-glucose 4,6-dehydratase with unknown function in humans but whose mutation-impairing activity causes the Catel–Manzke syndrome . These three enzymes catalyze NAD­(P) + -dependent oxidation of a sugar nucleotide 4′ hydroxyl but retain the resulting NAD­( P )H to catalyze a subsequent reductive step (SI Figure S7B–D).…”

Functions and mechanisms of protein lysine butyrylation (Kbu): Therapeutic implications in human diseases

“…Studies have indicated that O-GlcNAcylation may potentially ameliorate cancer, diabetes, and neurodegenerative diseases. 17 , 18 , 19 , 20 Moreover, PTMs play a role not only in regulating human diseases but also in plants. 21 , 22 , 23 , 24 Different PTMs that are related to each other and involved in dynamic transcriptional reprogramming play a role in fruit ripening.…”