O-GlcNAc Transferase – An Auxiliary Factor or a Full-blown Oncogene?

Abstract

The β-linked N-acetyl-D-glucosamine (GlcNAc) is a post-translational modification of serine and threonine residues catalyzed by the enzyme O-GlcNAc transferase (OGT). Increased OGT expression is a feature of most human cancers and inhibition of OGT decreases cancer cell proliferation. Anti-proliferative effects are attributed to post-translational modifications of known regulators of cancer cell proliferation, such as MYC, FOXM1 and EZH2. In general, OGT amplifies cell-specific phenotype, for example, OGT overexpression enhances reprogramming efficiency of mouse embryonic fibroblasts into stem cells. Genomewide screens suggest that certain cancers are particularly dependent on OGT, and understanding these addictions is important when considering OGT as a target for cancer therapy. The O-GlcNAc modification is involved in most cellular processes, which raises concerns of on-target undesirable effects of OGT targeting therapy. Yet, emerging evidence suggest that, much like proteasome inhibitors, specific compounds targeting OGT elicit selective anti-proliferative effects in cancer cells, and can prime malignant cells to other treatments. It is therefore essential to gain mechanistic insights on substrate specificity for OGT, develop reagents to more specifically enrich for O-GlcNAc modified proteins, identify O-GlcNAc 'readers' and develop OGT small molecule inhibitors. Here, we review the relevance of OGT in cancer progression and the potential targeting of this metabolic enzyme as a putative oncogene. Contrasting the functions of any candidate oncogene between normal and cancer cells is rarely done, but only by understanding the normal functions of a given factor, it is possible to understand these functions gone awry. Here we review oncogenic functions of OGT.

Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia

“…7 ). Homeostasis of O - GlcNAc through activities of OGT and OGA has been previously implicated in normal hematopoietic development 96 , 97 , in differentiation arrest of AML and Jurkat T‑cells 98 as well as in other cancers 99 . However, our study is the first to report that this modification is also essential for the survival of MLL-r B-ALL cells.…”

DNA Polymerase Iota Promotes Esophageal Squamous Cell Carcinoma Proliferation Through Erk-OGT-Induced G6PD Overactivation

“…OGT promotes protein O-GlcNAcylation ( 37 , 38 ) and has been found to be upregulated in most cancers including ESCC ( 39 , 40 ). In the present study, we found that total O-GlcNAcylation level is correlated with OGT expression and poor patient prognosis (R = 0.43, Figures 3F, G ).…”

The glycobiological landscape of breast cancer: insights into galectins and O-GlcNAc homeostasis-related genes

“…Protein O-GlcNAcylation is globally elevated in breast cancer and other malignancies that targets multiple transcription factors and alters gene expression pro les in the favour of metastatic and cancer stem cells [20,21,[29][30][31]. Therefore, cell stemness-related transcription factors were also included in our analysis in the context of their functions associated with high O-GlcNAc enrichment in tumors.…”