O-GlcNAcylation and Metabolic Reprograming in Cancer

Abstract

Although cancer metabolism has received considerable attention over the past decade, our knowledge on its specifics is still fragmentary. Altered cellular metabolism is one of the most important hallmarks of cancer. Cancer cells exhibit aberrant glucose metabolism characterized by aerobic glycolysis, a phenomenon known as Warburg effect. Accelerated glucose uptake and glycolysis are main characteristics of cancer cells that allow them for intensive growth and proliferation. Accumulating evidence suggests that O-GlcNAc transferase (OGT), an enzyme responsible for modification of proteins with N-acetylglucosamine, may act as a nutrient sensor that links hexosamine biosynthesis pathway to oncogenic signaling and regulation of factors involved in glucose and lipid metabolism. Recent studies suggest that metabolic reprograming in cancer is connected to changes at the epigenetic level. O-GlcNAcylation seems to play an important role in the regulation of the epigenome in response to cellular metabolic status. Through histone modifications and assembly of gene transcription complexes, OGT can impact on expression of genes important for cellular metabolism. This paper reviews recent findings related to O-GlcNAc-dependent regulation of signaling pathways, transcription factors, enzymes, and epigenetic changes involved in metabolic reprograming of cancer.

Protein Sialylation Regulates a Gene Expression Signature that Promotes Breast Cancer Cell Pathogenicity

“…27 In addition, O-GlcNAc modifications have also been shown to control transcriptional programs through modification of transcriptional complexes or epigenetic regulation. 28 Our data thus far point to indirect transcriptional regulation of many genes through impairing protein sialylation, including sialylated proteins EGFR and CD44, which are well-studied in the context of cancer. We postulate that reduced protein sialylation, perhaps of a particular yet unidentified protein, may lead to lysosomal or proteasome-mediated degradation and in turn cause the observed transcriptional signature we report here.…”

Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?

“…2b). UDP-GlcNAc is a sugar donor for the glycosylation of proteins 13–15 . In glycogenesis, glycogen, a branched polymer of glucose that functions as a repository of glucose units, is synthesized from G6P (FIG.…”

Silencing the Nucleocytoplasmic O-GlcNAc Transferase Reduces Proliferation, Adhesion, and Migration of Cancer and Fetal Human Colon Cell Lines

“…Deregulation of O -GlcNAcylation dynamics actively participates in tumorigenesis and in the etiology of cancer ( 5 ). A synergy between unhealthy diet and cancer development is proposed because of the status of OGT’s natural substrate, UDP-GlcNAc, which is positioned at the crossroad of metabolic pathways ( 6 – 8 ). Moreover, glucose transport and consumption is upregulated in cancer cells.…”