Abstract
Simple SummaryDespite the rapid advancement in immunotherapy and targeted agents, many patients diagnosed with cancer have poor prognosis with dismal overall survival. One of the key hallmarks of cancer is the ability of cancer cells to reprogram their energy metabolism. O-GlcNAcylation is an emerging potential mechanism for cancer cells to induce proliferation and progression of tumor cells and resistance to chemotherapy. This review summarizes the mechanism behind O-GlcNAcylation and discusses the role of O-GlcNAcylation, including its function with receptor tyrosine kinase and chemo-resistance in cancer, and immune response to cancer and as a prognostic factor. Further pre-clinical studies on O-GlcNAcylation are warranted to assess the clinical efficacy of agents targeting O-GlcNAcylation.Cancer cells are able to reprogram their glucose metabolism and retain energy via glycolysis even under aerobic conditions. They activate the hexosamine biosynthetic pathway (HBP), and the complex interplay of O-linked N-acetylglucosaminylation (O-GlcNAcylation) via deprivation of nutrients or increase in cellular stress results in the proliferation, progression, and metastasis of cancer cells. Notably, cancer is one of the emerging diseases associated with O-GlcNAcylation. In this review, we summarize studies that delineate the role of O-GlcNAcylation in cancer, including its modulation in metastasis, function with receptor tyrosine kinases, and resistance to chemotherapeutic agents, such as cisplatin. In addition, we discuss the function of O-GlcNAcylation in eliciting immune responses associated with immune surveillance in the tumor microenvironment. O-GlcNAcylation is increasingly accepted as one of the key players involved in the activation and differentiation of T cells and macrophages. Finally, we discuss the prognostic role of O-GlcNAcylation and potential therapeutic agents such as O-linked β-N-acetylglucosamine-transferase inhibitors, which may help overcome the resistance mechanism associated with the reprogramming of glucose metabolism.
Highlights
One of the pivotal hallmarks of cancer is reprogramming energy metabolism in cancer cells [1]
Contrary to other post-translational modification (PTM) that are regulated by diverse enzymes, O-GlcNAcylation is controlled by a single pair of enzymes, O-GlcNAc transferase (OGT) and OGA, which recognize hundreds of protein substrates [6,8] (Figure 1)
tricarboxylic acid cycle (TCA), Tricarboxylic acid cycle; OXPHOS, Oxidative phosphorylation; HBP, hexosamine biosynthetic pathway GFAT1, hexosamine biosynthetic pathway; GNAT, N-acetyltransferase; AGM, N-acetylphosphoglucosamine mutase; AGX, UDP-N-acetylhexosamine pyrophosphorylase; OGA, O-GlcNAcase; OGT, O-GlcNAc-transferase. Under specific condition such as glucose deprivation and fasting, OGT substrate recognition may be mediated by proteins, including p38 mitogen-activated protein kinase (MAPK), host cell factor 1 (HCF1), and OGA, which act as adaptor proteins in their receptive substrates of neurofilament H (NFH), peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha (PGC1α), and pyruvate kinase M2 (PKM2), respectively [24,25,26]
Summary
One of the pivotal hallmarks of cancer is reprogramming energy metabolism in cancer cells [1]. Mitochondrial oxidative phosphorylation produces ATP with approximately 18-fold higher efficiency than aerobic glycolysis, cancer cells manage to compensate energy metabolism by the HBP [4,5]. UDP-GlcNAc transfers O-linked-β-N-acetylglucosamine (O-GlcNAc) to the enzyme O-GlcNAc transferase (OGT), which attaches O-GlcNAc moieties to the serine and/or threonine residues of substrate proteins, including cytoplasmic, nuclear and mitochondrial proteins [8]. This process results in post-translational modification (PTM) of the substrate proteins known as called O-GlcNAcylation [9]. We discuss the role of O-GlcNAcylation from the perspectives of cancer, including metastasis, receptor tyrosine kinases (RTKs), resistance to chemotherapy, prognostic marker, tumor microenvironment, and the potential targeting of cellular O-GlcNAcylation as cancer therapeutics
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