O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth.
Acetylation
Acetylglucosamine
/ metabolism
Animals
Antigens, Neoplasm
/ metabolism
Carrier Proteins
/ metabolism
Cell Line, Tumor
Datasets as Topic
Disease Progression
Female
Gene Expression Profiling
Glycolysis
HEK293 Cells
Histone Acetyltransferases
/ metabolism
Humans
Hyaluronoglucosaminidase
/ metabolism
Male
Membrane Proteins
/ metabolism
Mice
N-Acetylglucosaminyltransferases
/ metabolism
Neoplasm Grading
Neoplasm Staging
Neoplasms
/ metabolism
Protein Processing, Post-Translational
Thyroid Hormones
/ metabolism
Tissue Array Analysis
Up-Regulation
Xenograft Model Antitumor Assays
Thyroid Hormone-Binding Proteins
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
18
06
2017
accepted:
18
06
2019
revised:
12
05
2019
pubmed:
11
9
2019
medline:
20
6
2020
entrez:
11
9
2019
Statut:
ppublish
Résumé
Cancer cells are known to adopt aerobic glycolysis in order to fuel tumor growth, but the molecular basis of this metabolic shift remains largely undefined. O-GlcNAcase (OGA) is an enzyme harboring O-linked β-N-acetylglucosamine (O-GlcNAc) hydrolase and cryptic lysine acetyltransferase activities. Here, we report that OGA is upregulated in a wide range of human cancers and drives aerobic glycolysis and tumor growth by inhibiting pyruvate kinase M2 (PKM2). PKM2 is dynamically O-GlcNAcylated in response to changes in glucose availability. Under high glucose conditions, PKM2 is a target of OGA-associated acetyltransferase activity, which facilitates O-GlcNAcylation of PKM2 by O-GlcNAc transferase (OGT). O-GlcNAcylation inhibits PKM2 catalytic activity and thereby promotes aerobic glycolysis and tumor growth. These studies define a causative role for OGA in tumor progression and reveal PKM2 O-GlcNAcylation as a metabolic rheostat that mediates exquisite control of aerobic glycolysis.
Identifiants
pubmed: 31501520
doi: 10.1038/s41388-019-0975-3
pii: 10.1038/s41388-019-0975-3
pmc: PMC7107572
mid: NIHMS1532844
doi:
Substances chimiques
Antigens, Neoplasm
0
Carrier Proteins
0
Membrane Proteins
0
Thyroid Hormones
0
Histone Acetyltransferases
EC 2.3.1.48
N-Acetylglucosaminyltransferases
EC 2.4.1.-
OGT protein, human
EC 2.4.1.255
OGA protein, human
EC 3.2.1.169
Hyaluronoglucosaminidase
EC 3.2.1.35
Acetylglucosamine
V956696549
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
560-573Subventions
Organisme : NIDDK NIH HHS
ID : P01 DK057751
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK089098
Pays : United States
Références
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
pubmed: 21376230
Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012;21:297–308.
pubmed: 22439925
pmcid: 3311998
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.
Hart GW, Housley MP, Slawson C. Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature. 2007;446:1017–22.
pubmed: 17460662
Yang X, Qian K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol. 2017;18:452–65.
pubmed: 28488703
pmcid: 5667541
Bond MR, Hanover JA. O-GlcNAc cycling: a link between metabolism and chronic disease. Annu Rev Nutr. 2013;33:205–29.
pubmed: 23642195
Ong Q, Han W, Yang X. O-GlcNAc as an integrator of signaling pathways. Front Endocrinol. 2018;9:599.
Ruan HB, Singh JP, Li MD, Wu J, Yang X. Cracking the O-GlcNAc code in metabolism. Trends Endocrinol Metab. 2013;24:301–9.
pubmed: 23647930
pmcid: 3783028
Li MD, Ruan HB, Hughes ME, Lee JS, Singh JP, Jones SP, et al. O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination. Cell Metab. 2013;17:303–10.
pubmed: 23395176
pmcid: 3647362
Ruan HB, Han X, Li MD, Singh JP, Qian K, Azarhoush S, et al. O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1alpha stability. Cell Metab. 2012;16:226–37.
pubmed: 22883232
pmcid: 3480732
Ruan HB, Dietrich MO, Liu ZW, Zimmer MR, Li MD, Singh JP, et al. O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell. 2014;159:306–17.
pubmed: 25303527
pmcid: 4509746
Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, So WV, et al. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature. 2008;451:964–9.
pubmed: 18288188
Zhang K, Yin R, Yang X. O-GlcNAc: a bittersweet switch in liver. Front Endocrinol. 2014;5:221.
Caldwell SA, Jackson SR, Shahriari KS, Lynch TP, Sethi G, Walker S, et al. Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1. Oncogene. 2010;29:2831–42.
pubmed: 20190804
Qian K, Wang S, Fu M, Zhou J, Singh JP, Li MD. et al. Transcriptional regulation of O-GlcNAc homeostasis is disrupted in pancreatic cancer. J Biol Chem. 2018;293:13989–4000.
pubmed: 30037904
pmcid: 6130940
Singh JP, Zhang K, Wu J, Yang X. O-GlcNAc signaling in cancer metabolism and epigenetics. Cancer Lett. 2015;356:244–50.
pubmed: 24769077
Slawson C, Hart GW. O-GlcNAc signalling: implications for cancer cell biology. Nat Rev Cancer. 2011;11:678–84.
pubmed: 21850036
pmcid: 3291174
Yang YR, Jang HJ, Yoon S, Lee YH, Nam D, Kim IS, et al. OGA heterozygosity suppresses intestinal tumorigenesis in Apc(min/+) mice. Oncogenesis. 2014;3:e109.
pubmed: 25000257
pmcid: 4150210
Ferrer CM, Lynch TP, Sodi VL, Falcone JN, Schwab LP, Peacock DL, et al. O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway. Mol Cell. 2014;54:820–31.
pubmed: 24857547
pmcid: 4104413
Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA 3rd, et al. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science. 2012;337:975–80.
pubmed: 22923583
pmcid: 3534962
Hayakawa K, Hirosawa M, Tabei Y, Arai D, Tanaka S, Murakami N, et al. Epigenetic switching by the metabolism-sensing factors in the generation of orexin neurons from mouse embryonic stem cells. J Biol Chem. 2013;288:17099–110.
pubmed: 23625921
pmcid: 3682516
Toleman C, Paterson AJ, Whisenhunt TR, Kudlow JE. Characterization of the histone acetyltransferase (HAT) domain of a bifunctional protein with activable O-GlcNAcase and HAT activities. J Biol Chem. 2004;279:53665–73.
pubmed: 15485860
Yang W, Lu Z. Regulation and function of pyruvate kinase M2 in cancer. Cancer Lett. 2013;339:153–8.
pubmed: 23791887
pmcid: 3950276
Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol. 2012;8:839–47.
pubmed: 22922757
pmcid: 3711671
Ashizawa K, Willingham MC, Liang CM, Cheng SY. In vivo regulation of monomer-tetramer conversion of pyruvate kinase subtype M2 by glucose is mediated via fructose 1,6-bisphosphate. J Biol Chem. 1991;266:16842–6.
pubmed: 1885610
Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230–3.
pubmed: 18337823
Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature. 2008;452:181–6.
pubmed: 18337815
Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K, et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal. 2009;2:ra73.
pubmed: 19920251
pmcid: 2812789
Lv L, Li D, Zhao D, Lin R, Chu Y, Zhang H, et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol Cell. 2011;42:719–30.
pubmed: 21700219
pmcid: 4879880
Lv L, Xu YP, Zhao D, Li FL, Wang W, Sasaki N, et al. Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization. Mol Cell. 2013;52:340–52.
pubmed: 24120661
pmcid: 4183148
Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Investig. 2008;118:3930–42.
pubmed: 19033663
Whisenhunt TR, Yang X, Bowe DB, Paterson AJ, Van Tine BA, Kudlow JE. Disrupting the enzyme complex regulating O-GlcNAcylation blocks signaling and development. Glycobiology. 2006;16:551–63.
pubmed: 16505006
Krzeslak A, Forma E, Bernaciak M, Romanowicz H, Brys M. Gene expression of O-GlcNAc cycling enzymes in human breast cancers. Clin Exp Med. 2012;12:61–5.
pubmed: 21567137
He Y, Roth C, Turkenburg JP, Davies GJ. Three-dimensional structure of a Streptomyces sviceus GNAT acetyltransferase with similarity to the C-terminal domain of the human GH84 O-GlcNAcase. Acta Crystallogr D Biol Crystallogr. 2014;70:186–95.
pubmed: 24419391
Rao FV, Schuttelkopf AW, Dorfmueller HC, Ferenbach AT, Navratilova I, van Aalten DM. Structure of a bacterial putative acetyltransferase defines the fold of the human O-GlcNAcase C-terminal domain. Open Biol. 2013;3:130021.
pubmed: 24088714
pmcid: 3814719
Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol. 2012;14:1295–304.
pubmed: 23178880
pmcid: 3511602
Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 2010;329:1492–9.
pmcid: 3030121
Bowe DB, Sadlonova A, Toleman CA, Novak Z, Hu Y, Huang P, et al. O-GlcNAc integrates the proteasome and transcriptome to regulate nuclear hormone receptors. Mol Cell Biol. 2006;26:8539–50.
pubmed: 16966374
pmcid: 1636782
Luo J, Deng ZL, Luo X, Tang N, Song WX, Chen J, et al. A protocol for rapid generation of recombinant adenoviruses using the AdEasy system. Nat Protoc. 2007;2:1236–47.
pubmed: 17546019
Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nat Protoc. 2006;1:2315–9.
pubmed: 17406473
Patel AB, de Graaf RA, Mason GF, Rothman DL, Shulman RG, Behar KL. The contribution of GABA to glutamate/glutamine cycling and energy metabolism in the rat cortex in vivo. Proc Natl Acad Sci USA. 2005;102:5588–93.
pubmed: 15809416