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

TitleO-GlcNAc Transferase - An Auxiliary Factor or a Full-blown Oncogene?
Publication TypeJournal Article
Year of Publication2021
AuthorsItkonen HM, Loda M, Mills IG
JournalMol Cancer Res
Date Published2021 04

The β-linked N-acetyl-d-glucosamine (GlcNAc) is a posttranslational 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. Antiproliferative effects are attributed to posttranslational 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. Genome-wide 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 antiproliferative 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.

Alternate JournalMol Cancer Res
PubMed ID33472950
Grant ListCEO13_2-004 / PCUK_ / Prostate Cancer UK / United Kingdom
R01 CA187918 / CA / NCI NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States
Related Faculty: 
Massimo Loda, M.D.

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