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Emerging Role of the Hexosamine Biosynthetic Pathway in Cancer Neha M

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Emerging Role of the Hexosamine Biosynthetic Pathway in Cancer Neha M Akella et al. BMC Biology (2019) 17:52 https://doi.org/10.1186/s12915-019-0671-3 REVIEW Open Access Fueling the fire: emerging role of the hexosamine biosynthetic pathway in cancer Neha M. Akella, Lorela Ciraku and Mauricio J. Reginato* “ ” Abstract conditions [2]. This switch, termed the Warburg effect , funnels glycolytic intermediates into pathways that produce Altered metabolism and deregulated cellular energetics nucleosides, amino acids, macromolecules, and organelles are now considered a hallmark of all cancers. Glucose, required for rapid cell proliferation [3]. Unlike normal cells, glutamine, fatty acids, and amino acids are the primary cancer cells reprogram cellular energetics as a result of drivers of tumor growth and act as substrates for the oncogenic transformations [4]. The hexosamine biosyn- hexosamine biosynthetic pathway (HBP). The HBP thetic pathway utilizes up to 2–5% of glucose that enters a culminates in the production of an amino sugar uridine non-cancer cell and along with glutamine, acetyl- diphosphate N-acetylglucosamine (UDP-GlcNAc) that, coenzyme A (Ac-CoA) and uridine-5′-triphosphate (UTP) along with other charged nucleotide sugars, serves as the are used to produce the amino sugar UDP-GlcNAc [5]. basis for biosynthesis of glycoproteins and other The HBP and glycolysis share the first two steps and di- glycoconjugates. These nutrient-driven post-translational verge at fructose-6-phosphate (F6P) (Fig. 1). Glutamine modifications are highly altered in cancer and regulate fructose-6-phosphate amidotransferase (GFAT) converts protein functions in various cancer-associated processes. F6P and glutamine to glucosamine-6-phosphate and glu- In this review, we discuss recent progress in tamate in the rate-limiting step of HBP [6]. Glucosamine understanding the mechanistic relationship between the entering the cell is also converted to glucosamine-6- HBP and cancer. phosphate using GNK (GlcNAc kinase). In the next step, Keywords: Hexosamine biosynthetic pathway, the enzyme glucosamine-phosphate N-acetyltransferase Glycosylation, UDP-GlcNAc, O-GlcNAcylation, O-GlcNAc (GNPNAT) catalyzes Ac-CoA and glucosamine-6- transferase, Cancer, Metabolism phosphate to generate N-acetylglucosamine-6-phosphate (GlcNAc-6P) and CoA. This is followed by GlcNAc phos- phomutase (PGM3/AGM1)-mediated isomerization into Hexosamine biosynthetic pathway GlcNAc-1-phosphate (GlcNAc-1-P). Finally, UTP and Nutrient sensing plays a major part in maintaining cellular GlcNAc-1Pz produce UDP-GlcNAc through UDP-N- homeostasis and regulating metabolic processes. The hexo- acetylglucosamine pyrophosphorylase (UAP1/AGX1) en- samine biosynthetic pathway (HBP) and its end product zyme [6, 7]. Since the HBP utilizes major macromolecules uridine diphosphate N-acetyl glucosamine (UDP-GlcNAc) such as nucleotides, amino acids, carbohydrates, and lipids are important regulators of cell signaling that favor tumor to produce UDP-GlcNAc, cells may use it as a ‘sensor’ of promotion. Alterations in nutrient uptake homeostasis energy availability that influences a large number of func- affect cellular energetics inducing cellular stress [1]. Cell tional targets that contribute to cancer phenotypes (Fig. 2). growth is primarily supported by growth factor-driven glu- UDP-GlcNAc is required for both O-GlcNAcylation, cose and glutamine intake, which form building blocks for which is a single sugar conjugation, catalyzed by O-Glc biosynthesis. Cells under aerobic conditions utilize oxida- NAc transferase (OGT) in the cytoplasm, nucleus, and tive phosphorylation in mitochondria to sustain energy de- mitochondria [8], and O- and N-linked glycosylation of mands. Otto Warburg noticed that cancer cells utilize far proteins occurring in the endoplasmic reticulum (ER) more glucose than normal cells and reprogram their me- and the Golgi apparatus [9]. N-linked glycosylation takes tabolism largely to glycolysis even in oxygen-rich place co-translationally in the ER and further N-glycan branching is added in the Golgi by four N- * Correspondence: [email protected] acetylglucosaminyltransferases (MGAT) on cell surface Department of Biochemistry and Molecular Biology, Drexel University College glycoconjugate proteins [7] (Fig. 1). UDP-GlcNAc can of Medicine, Philadelphia, PA 19102, USA © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Akella et al. BMC Biology (2019) 17:52 Page 2 of 14 Fig. 1. The hexosamine biosynthetic pathway. Glucose enters the cell and undergoes two-step conversion to fructose-6P (fructose-6-phosphate), after which approximately 95% of it proceeds to glycolysis and 3–5% of it is converted to glucosamine-6P (glucosamine-6-phosphate) by the enzyme GFAT (glutamine:fructose-6-phosphate amidotransferase), utilizing glutamine that enters the cell. GFAT catalyzes the first and rate-limiting step in the formation of hexosamine products and thus is a key regulator of HBP. GNA1/GNPNAT1 (glucosamine-6-phosphate N-acetyltransferase) then converts glucosamine-6P (which can also be made by glucosamine entering the cell) into GlcNAc-6P (N-acetylglucosamine-6-Phosphate), also utilizing acetyl-CoA that is made from fatty acid metabolism. This is then converted to GlcNAc-1P (N-acetylglucosamine 1-phosphate) by PGM3/AGM1 (phosphoglucomutase) and further to UDP-GlcNAc (uridine diphosphate N-acetylglucosamine) by UAP/AGX1 (UDP-N- acetylhexosamine pyrophosphorylase), utilizing UTP from the nucleotide metabolism pathway. UDP-GlcNAc is then used for N-linked and O- linked glycosylation in the ER and Golgi and for O-GlcNAc modification of nuclear and cytoplasmic proteins by OGT (O-GlcNAc transferase). OGA (O-GlcNAcase) catalyzes the removal of O-GlcNAc and adds back GlcNAc to the HBP pool for re-cycling through salvage pathway (Fig. 3) also be synthesized in a salvage pathway (Fig. 3) through proteins solely via OGT, whereas O-GlcNAcase (OGA) phosphorylation of the GlcNAc molecule, a by-product is the enzyme responsible for the removal of this revers- of lysosomal degradation of glycoconjugates, by GlcNAc ible sugar modification. O-GlcNAc modifies a wide var- kinase (NAGK), thus bypassing GFAT [10]. GALE iety of proteins, including metabolic enzymes, (UDP-glucose 4-epimerase/UDP-galactose 4-epimerase) transcription factors, and signaling molecules (Fig. 4) creates another route to generate UDP-GlcNAc through [13, 14]. The extent of protein O-GlcNAcylation can interconversion of UDP-GalNAc or through UDP- also be regulated by UDP-GlcNAc localization and glucose [11]. UDP-GlcNAc and F6P are converted to transport into different compartments and organelles. ManNAc-6-phosphate through GNE (UDP-GlcNAc 2- The nucleus and cytoplasmic levels of UPD-GlcNAc are epimerase/ManNAc kinase) and MPI (Mannose phos- affected by membrane permeability [14] while nucleotide phate isomerase), respectively, which goes on to further sugar transporters can actively transport UDP-GlcNAc produce glycoconjugates [6, 10, 12] as described in an into cellular organelles such as ER and Golgi [15] as well extended version of HBP in Fig. 3 that highlights inter- as mitochondria [16]. In this review, we will highlight mediate steps not shown in Fig. 1. UDP-GlcNAc is used the latest discoveries into understanding the mechanistic as a substrate to covalently modify serine (Ser) and relationship between the HBP and regulation of cancer- threonine (Thr) residues of nuclear and cytoplasmic associated phenotypes. Akella et al. BMC Biology (2019) 17:52 Page 3 of 14 Fig. 2. The HBP is at the center of many cancer processes. The HBP is highly dependent on the nutrient state of a cell, as is evident from its heavy dependence on dietary molecules like glucose and glutamine as well as other metabolic pathways such as nucleotide and fatty acid metabolism. The highlighted substrate UDP-GlcNAc plays a key role in orchestrating many downstream glycosylation events that in turn control proteins and processes involved in cell signaling, metabolism, gene regulation, and EMT HBP and cancer was consistent with increased activity of HBP in matched Cancer cells upregulate HBP flux and UDP-GlcNAc levels tumor–benign pairs as detected when levels of UDP- through increased glucose and glutamine uptake as well GlcNAc were measured [27]. Paradoxically, castration- as in response to oncogenic-associated signals such as Ras resistant prostate cancers were found to have decreased [17], mammalian target of rapamycin complex 2 HBP metabolites and GNPNAT1 expression, suggesting (mTORC2) [18, 19], and transforming growth factor beta metabolic re-wiring may occur during prostate cancer 1 (TGF-β)[20]. Both N-linked and O-linked glycosylation progression. Nevertheless, consistent with increased UDP- can be regulated by the HBP through nutrient sensing that GlcNAc levels in cancer cells, nearly all cancer cells exam- links to downstream cellular signaling [1, 13, 14]. An in- ined, including from prostate [28, 29], breast [30–32], lung crease or depletion of extracellular glucose and glutamine [33],
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