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.
Highlights
Since the time of Otto Warburg in the 1930s, scientists have been intrigued by the unique metabolic profile of cancer cells [1, 2]
Despite early conflicting viewpoints on the Warburg Effect, aerobic glycolysis stands at the center of cancer metabolism demonstrating its importance as an “Emerging Hallmark of Cancer” [4]
There are three major families of transcription factors (TFs) that contribute to epithelial–mesenchymal transition (EMT) and may be general drivers of cancer (Figure 1B): [1] the zinc finger protein SNAIL family (SNAI1, SNAI2, and SNAI3) [32], [2] the basic Helix-LoopHelix proteins TWIST1 and TWIST2 [33], and [3] the zinc-finger E-box binding (ZEB) family of TFs [34]
Summary
Since the time of Otto Warburg in the 1930s, scientists have been intrigued by the unique metabolic profile of cancer cells [1, 2]. The major characteristics of EMT include loss of cellular adhesion, reorganization of cytoskeleton, loss of cellular polarity, and a switch from epithelial to mesenchymal gene expression [18] Many of these EMT pathways are activated by extracellular signaling, highlighting the importance of the tumor microenvironment for the induction of EMT. There are three major families of transcription factors (TFs) that contribute to EMT and may be general drivers of cancer (Figure 1B): [1] the zinc finger protein SNAIL family (SNAI1, SNAI2, and SNAI3) [32], [2] the basic Helix-LoopHelix (bHLH) proteins TWIST1 and TWIST2 [33], and [3] the zinc-finger E-box binding (ZEB) family of TFs [34] These TFs are evolutionarily conserved and critical for development. The data discussed above suggest that the EMT program promotes many cancer cell phenotypes leading to malignancy
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