Hijacking the Hexosamine Biosynthetic Pathway to Promote EMT-Mediated Neoplastic Phenotypes

Abstract

The epithelial–mesenchymal transition (EMT) is a highly conserved program necessary for orchestrating distant cell migration during embryonic development. Multiple studies in cancer have demonstrated a critical role for EMT during the initial stages of tumorigenesis and later during tumor invasion. Transcription factors (TFs) such as SNAIL, TWIST, and ZEB are master EMT regulators that are aberrantly overexpressed in many malignancies. Recent evidence correlates EMT-related transcriptomic alterations with metabolic reprograming in cancer. Metabolic alterations may allow cancer to adapt to environmental stressors, supporting the irregular macromolecular demand of rapid proliferation. One potential metabolic pathway of increasing importance is the hexosamine biosynthesis pathway (HBP). The HBP utilizes glycolytic intermediates to generate the metabolite UDP–GlcNAc. This and other charged nucleotide sugars serve as the basis for biosynthesis of glycoproteins and other glycoconjugates. Recent reports in the field of glycobiology have cultivated great curiosity within the cancer research community. However, specific mechanistic relationships between the HBP and fundamental pathways of cancer, such as EMT, have yet to be elucidated. Altered protein glycosylation downstream of the HBP is well positioned to mediate many cellular changes associated with EMT including cell–cell adhesion, responsiveness to growth factors, immune system evasion, and signal transduction programs. Here, we outline some of the basics of the HBP and putative roles the HBP may have in driving EMT-related cancer processes. With novel appreciation of the HBP’s connection to EMT, we hope to illuminate the potential for new therapeutic targets of cancer.

O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis

“…Using complimentary genetic and pharmacologic methods in vitro and in vivo, we showed for the first time that the HBP was required for Kras G12D -induced lung tumorigenesis and lung tumor maintenance. As the HBP is required for various glycosylation processes, such as protein N-linked glycosylation, O-GlcNAcylation, and glycolipid synthesis (31,49), it was important for us to examine whether this HBP requirement constituted N-linked downstream events or O-GlcNAcylation. Using more specific genetic (OGT and OGA manipulation) and pharmacologic (TT04) tools, we established that O-GlcNAcylation was not only required for Kras G12D -induced lung tumorigenesis and tumor maintenance in vitro and in vivo, but was also sufficient to accelerate Kras G12D -induced lung tumorigenesis.…”

“…O-GlcNAcylation is required to suppress senescence. The HBP produces the nucleotide sugar UDP-GlcNAc, which can be utilized in multiple pathways, including both N-linked and O-linked protein glycosylations ( Figure 5A), which regulate protein stability and activity (31)(32)(33). We performed reversed-phase HPLC to measure UDP-GlcNAc levels in isogenic human NSCLC cell lines (A549, H358, and H460) with and without Twist1 overexpression.…”

Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition

“…O-GlcNAc can be considered one of the links between glucose metabolism and the acquisition of EMT features (Park et al, 2010;Alisson-Silva et al, 2013). O-GlcNAc influences cell plasticity modifying key proteins involved in EMT process (Taparra et al, 2016). One of the most studied EMT-related molecules is the intercellular adherence protein E-cadherin, which is currently thought to be a suppressor of tumor invasion.…”

Antioxidant Effects and Mechanisms of Medicinal Plants and Their Bioactive Compounds for the Prevention and Treatment of Type 2 Diabetes: An Updated Review

“…Abnormally high blood sugar levels and insulin resistance-induced fatty oxidation plays a key role in the onset and advancement of diabetic complications via increasing the flux of fructose-6-phosphate into the hexosamine biosynthetic pathway [76,77]. This abnormal blood glucose level triggers the premature activation of some metabolic pathways, which in turn causes the usual expression of certain cytokines such as CTGF, ICAM-1, PAI-1, TGF-β, TNF-α, and VCAM-1, which are involved in the development of lesion [78,79]. Upon the absorption of glucose by cells, a majority are digested and shoved via glycogen synthesis, metabolism of the pentose phosphate, and glycolysis; furthermore, approximately 1-3% of glucose also go into the hexosamine biosynthetic pathway [79,80].…”

“…This abnormal blood glucose level triggers the premature activation of some metabolic pathways, which in turn causes the usual expression of certain cytokines such as CTGF, ICAM-1, PAI-1, TGF-β, TNF-α, and VCAM-1, which are involved in the development of lesion [78,79]. Upon the absorption of glucose by cells, a majority are digested and shoved via glycogen synthesis, metabolism of the pentose phosphate, and glycolysis; furthermore, approximately 1-3% of glucose also go into the hexosamine biosynthetic pathway [79,80]. According to Qin et al [81], the excessive shunting of intracellular glucose via the hexosamine biosynthetic pathway has been implicated in a myriad of diabetic complications.…”