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

Taparra K, Tran PT, Zachara NE - Front Oncol (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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.

No MeSH data available.


Related in: MedlinePlus

The hexosamine biosynthetic pathway (HBP) and glycosylated EMT targets. (A) First, the rate limiting enzyme of the HBP, glutamine:fructose-6-phosphate transaminase (GFAT), uses glutamine (Gln) as an amine donor to convert Fru-6P into glucosamine-6-P (GlcN-6P). Second, glucosamine-phosphate N-acetyltransferase (GNPNAT) N-acetylates GlcN-6P in an acetyl-CoA-mediated reaction to form N-acetylglucosamine-6-P (GlcNAc-6P). Third, phosphoglucomutase (PGM) isomerizes GlcNAc-6P to the highly active GlcNAc-1P. The final step is catalyzed by UDP–N-acetylglucosamine pyrophosphorylase (UAP1) and charges GlcNAc-1P with UDP to form uridine-5′-diphosphate-N-acetylglucosamine (UDP–GlcNAc). (B) UDP–GlcNAc (depicted as a blue square) is essential for N-glycosylation processing and elongation. One critical pivot point includes the branching of complex N-glycans. Inhibiting this process with a bisecting GlcNAc is associated with tumor suppressive phenotypes. In contrast, cancers have aberrant expression of glycosyltransferases responsible for branching and elongating complex N-glycans. (C) Many of the proteins commonly associated with promoting EMT are modified by glycans containing GlcNAc and are found on the cell surface. Hyaluronan, a glycosaminoglycan, is also found extracellularly and is a polymer of glucuronic acid and N-acetylglucosamine. Many nuclear, cytoplasmic and mitochondrial proteins are modified by monosaccharides of O-linked N-acetylglucosamine (O-GlcNAc), including many transcription factors, which appear to be stabilized by glycosylation (63). Numerous studies have identified various cancers with elevated levels of pan-O-GlcNAcylation (64).
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Figure 2: The hexosamine biosynthetic pathway (HBP) and glycosylated EMT targets. (A) First, the rate limiting enzyme of the HBP, glutamine:fructose-6-phosphate transaminase (GFAT), uses glutamine (Gln) as an amine donor to convert Fru-6P into glucosamine-6-P (GlcN-6P). Second, glucosamine-phosphate N-acetyltransferase (GNPNAT) N-acetylates GlcN-6P in an acetyl-CoA-mediated reaction to form N-acetylglucosamine-6-P (GlcNAc-6P). Third, phosphoglucomutase (PGM) isomerizes GlcNAc-6P to the highly active GlcNAc-1P. The final step is catalyzed by UDP–N-acetylglucosamine pyrophosphorylase (UAP1) and charges GlcNAc-1P with UDP to form uridine-5′-diphosphate-N-acetylglucosamine (UDP–GlcNAc). (B) UDP–GlcNAc (depicted as a blue square) is essential for N-glycosylation processing and elongation. One critical pivot point includes the branching of complex N-glycans. Inhibiting this process with a bisecting GlcNAc is associated with tumor suppressive phenotypes. In contrast, cancers have aberrant expression of glycosyltransferases responsible for branching and elongating complex N-glycans. (C) Many of the proteins commonly associated with promoting EMT are modified by glycans containing GlcNAc and are found on the cell surface. Hyaluronan, a glycosaminoglycan, is also found extracellularly and is a polymer of glucuronic acid and N-acetylglucosamine. Many nuclear, cytoplasmic and mitochondrial proteins are modified by monosaccharides of O-linked N-acetylglucosamine (O-GlcNAc), including many transcription factors, which appear to be stabilized by glycosylation (63). Numerous studies have identified various cancers with elevated levels of pan-O-GlcNAcylation (64).

Mentions: Since the 1950s, cancer has been notorious for its addiction to glucose and glutamine (7, 56–58). Upon depletion of these carbon sources in cancer cell culture media, cellular growth is abrogated. Both glucose and glutamine (Gln) are essential for the first committed step and rate-limiting step of the HBP, the conversion of fructose-6-phosphate (Fru-6P) to glucosamine-6-phosphate. Approximately 2–5% of glucose (in adipocytes) is shunted through the HBP (59). Demonstrating the importance of extracellular glucose concentrations on the HBP, glucose starvation reduces UDP–GlcNAc levels (60, 61). Conversely, elevating extracellular glucose concentrations results in increased flux through the HBP (62). Figure 2A summarizes the four key enzymatic steps of the HBP:(1)


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

Taparra K, Tran PT, Zachara NE - Front Oncol (2016)

The hexosamine biosynthetic pathway (HBP) and glycosylated EMT targets. (A) First, the rate limiting enzyme of the HBP, glutamine:fructose-6-phosphate transaminase (GFAT), uses glutamine (Gln) as an amine donor to convert Fru-6P into glucosamine-6-P (GlcN-6P). Second, glucosamine-phosphate N-acetyltransferase (GNPNAT) N-acetylates GlcN-6P in an acetyl-CoA-mediated reaction to form N-acetylglucosamine-6-P (GlcNAc-6P). Third, phosphoglucomutase (PGM) isomerizes GlcNAc-6P to the highly active GlcNAc-1P. The final step is catalyzed by UDP–N-acetylglucosamine pyrophosphorylase (UAP1) and charges GlcNAc-1P with UDP to form uridine-5′-diphosphate-N-acetylglucosamine (UDP–GlcNAc). (B) UDP–GlcNAc (depicted as a blue square) is essential for N-glycosylation processing and elongation. One critical pivot point includes the branching of complex N-glycans. Inhibiting this process with a bisecting GlcNAc is associated with tumor suppressive phenotypes. In contrast, cancers have aberrant expression of glycosyltransferases responsible for branching and elongating complex N-glycans. (C) Many of the proteins commonly associated with promoting EMT are modified by glycans containing GlcNAc and are found on the cell surface. Hyaluronan, a glycosaminoglycan, is also found extracellularly and is a polymer of glucuronic acid and N-acetylglucosamine. Many nuclear, cytoplasmic and mitochondrial proteins are modified by monosaccharides of O-linked N-acetylglucosamine (O-GlcNAc), including many transcription factors, which appear to be stabilized by glycosylation (63). Numerous studies have identified various cancers with elevated levels of pan-O-GlcNAcylation (64).
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Related In: Results  -  Collection

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Show All Figures
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Figure 2: The hexosamine biosynthetic pathway (HBP) and glycosylated EMT targets. (A) First, the rate limiting enzyme of the HBP, glutamine:fructose-6-phosphate transaminase (GFAT), uses glutamine (Gln) as an amine donor to convert Fru-6P into glucosamine-6-P (GlcN-6P). Second, glucosamine-phosphate N-acetyltransferase (GNPNAT) N-acetylates GlcN-6P in an acetyl-CoA-mediated reaction to form N-acetylglucosamine-6-P (GlcNAc-6P). Third, phosphoglucomutase (PGM) isomerizes GlcNAc-6P to the highly active GlcNAc-1P. The final step is catalyzed by UDP–N-acetylglucosamine pyrophosphorylase (UAP1) and charges GlcNAc-1P with UDP to form uridine-5′-diphosphate-N-acetylglucosamine (UDP–GlcNAc). (B) UDP–GlcNAc (depicted as a blue square) is essential for N-glycosylation processing and elongation. One critical pivot point includes the branching of complex N-glycans. Inhibiting this process with a bisecting GlcNAc is associated with tumor suppressive phenotypes. In contrast, cancers have aberrant expression of glycosyltransferases responsible for branching and elongating complex N-glycans. (C) Many of the proteins commonly associated with promoting EMT are modified by glycans containing GlcNAc and are found on the cell surface. Hyaluronan, a glycosaminoglycan, is also found extracellularly and is a polymer of glucuronic acid and N-acetylglucosamine. Many nuclear, cytoplasmic and mitochondrial proteins are modified by monosaccharides of O-linked N-acetylglucosamine (O-GlcNAc), including many transcription factors, which appear to be stabilized by glycosylation (63). Numerous studies have identified various cancers with elevated levels of pan-O-GlcNAcylation (64).
Mentions: Since the 1950s, cancer has been notorious for its addiction to glucose and glutamine (7, 56–58). Upon depletion of these carbon sources in cancer cell culture media, cellular growth is abrogated. Both glucose and glutamine (Gln) are essential for the first committed step and rate-limiting step of the HBP, the conversion of fructose-6-phosphate (Fru-6P) to glucosamine-6-phosphate. Approximately 2–5% of glucose (in adipocytes) is shunted through the HBP (59). Demonstrating the importance of extracellular glucose concentrations on the HBP, glucose starvation reduces UDP–GlcNAc levels (60, 61). Conversely, elevating extracellular glucose concentrations results in increased flux through the HBP (62). Figure 2A summarizes the four key enzymatic steps of the HBP:(1)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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.

No MeSH data available.


Related in: MedlinePlus