enhancer of zeste 2 polycomb repressive complex 2 subunit

Target id: 2654

Nomenclature: enhancer of zeste 2 polycomb repressive complex 2 subunit

Abbreviated Name: EZH2

Family: 2.1.1.43 Histone methyltransferases (HMTs)

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     enhancer of zeste 2 polycomb repressive complex 2 subunit has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 751 7q35-q36 EZH2 enhancer of zeste 2 polycomb repressive complex 2 subunit
Mouse - 746 6 B Ezh2 enhancer of zeste 2 polycomb repressive complex 2 subunit
Rat - 746 4q24 Ezh2 enhancer of zeste 2 polycomb repressive complex 2 subunit
Previous and Unofficial Names
KMT6 | enhancer of zeste homolog 2 (Drosophila)
Database Links
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
EPZ011989 Hs Inhibition >8.5 pKi 4
pKi >8.5 (Ki <3x10-9 M) [4]
EPZ005687 Hs Inhibition 7.6 pKi 9
pKi 7.6 (Ki 2.4x10-8 M) [9]
UNC1999 Hs Inhibition 8.7 pIC50 10
pIC50 8.7 (IC50 2x10-9 M) [10]
CPI-1205 Hs Inhibition 8.7 pIC50 24
pIC50 8.7 (IC50 2x10-9 M) [24]
Description: Cell-free biochemical assay
GSK343 Hs Inhibition 8.4 pIC50 25
pIC50 8.4 (IC50 4x10-9 M) [25]
EI1 Hs Inhibition 8.0 pIC50 17
pIC50 8.0 (IC50 9.4x10-9 M) [17]
GSK126 Hs Inhibition 8.0 pIC50 6,15
pIC50 8.0 (IC50 9.9x10-9 M) [6,15]
Description: Measured using expressed and purified five-member PRC2 protein complex (human Flag–EZH2,EED, SUZ12, AEBP2, RbAp48).
tazemetostat Hs Inhibition 8.0 pIC50 8
pIC50 8.0 (IC50 1.1x10-8 M) [8]
JQEZ5 Hs Inhibition 8.0 pIC50 22
pIC50 8.0 (IC50 1.1x10-8 M) [22]
Description: In vitro biochemical assay
Inhibitor Comments
In vitro GSK126 decreases histone trimethylation (H3K27me3) levels and is able to reactivate silenced PRC2 target genes, and inhibits proliferation of EZH2 mutant diffuse large B-cell lymphoma (DLBCL) cell lines [15]. In vivo GSK126 significantly inhibits the growth of EZH2 mutant DLBCL murine xenografts [15]. EI1 has similar inhibitory function [17]. These findings demonstrate that EZH2 is a druggable target susceptible to pharmacological intervention, with potential benefit in the treatment of EZH2 mutant lymphoma.
EPZ011989 (PubChem CID 73670548) is reported as a potent, orally bioavailable EZH2 inhibitor (Ki <3nM), with significant antiproliferative activity against human B cell lymphoma xenografts [4].
Immunopharmacology Comments
EZH2 is involved in hematopoietic stem cell proliferation and differentiation, thymopoiesis and lymphopoiesis, with notable participation in regulating the differentiation and function of T cells. This role suggests potential applications in immune-mediated conditions, including autoimmune disorders [23] and graft versus host disease (GvHD) [7].
Immuno Cell Type Associations
Immuno Cell Type:  T cells
Cell Ontology Term:   CD4-positive helper T cell (CL:0000492)
Comment:  EZH2 has an inhibitory role in the differentiation of Th1 and Th2 cells.
References:  7
Immuno Process Associations
Immuno Process:  Tissue repair
Immuno Process ID:  7
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration (GO:0014834) IEA
References: 
Physiological Functions
EZH2 regulates T cell polyfunctional effector cytokine expression and promotes their survival via Bcl-2 signaling.
Species:  Human
Tissue:  T cells
References:  26
EZH2 inhibits T cell Notch repressors.
Species:  Human
Tissue:  T cells
References:  26
Gene silencing: EZH2 is the methyltransferase component of the Polycomb repressive complex PRC2, which catalyzes the trimethylation of histone H3 at Lys27, resulting in epigenetic silencing of target genes.
Species:  Human
Tissue: 
References:  20
Clinically-Relevant Mutations and Pathophysiology
Disease:  Weaver syndrome
Disease Ontology: DOID:14731
OMIM: 277590
Orphanet: ORPHA3447
General Comments
EZH2 (or EZH1) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) [12] that catalyzes methylation of histone H3 lysine 27 (H3K27) [5,11-12,18]. EZH2 (KMT6) overexpression is implicated in tumorigenesis [1,14,19] and mutations within the catalytic (SET) domain of the enzyme, especially Tyr641 [16], have been identified in large B-cell lymphoma (DLBCL) and follicular lymphoma [3,13,21].

EZH2 inhibitors are being investigated as anti-cancer therapeutics, whereas EZH2 activating agents, driving inhibition of Th1 and Th2 cell differentiation, are suggested as novel interventions for the suppression of Th1- and Th2-dependent autoimmune diseases [7]. In addition, pharmacological inhibition of EZH1 and EZH2 has been shown to induce multiple inflammatory, stress, and antipathogen pathways, and to enhance recruitment of immune cells to virally infected cells in vitro, thereby creating a cellular antiviral state that was suppressive to infection by a range of DNA and RNA viruses [2]. EZH1/2 inhibitors exhibiting this experimental effect were GSK126, GSK343 and UNC1999. This work suggests that EZH1/2 inhibitors can induce a general antiviral defense mechanism.

References

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1. Albert M, Helin K. (2010) Histone methyltransferases in cancer. Semin. Cell Dev. Biol.21 (2): 209-20. [PMID:19892027]

2. Arbuckle JH, Gardina PJ, Gordon DN, Hickman HD, Yewdell JW, Pierson TC, Myers TG, Kristie TM. (2017) Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens. MBio8 (4). [PMID:28811345]

3. Bödör C, Grossmann V, Popov N, Okosun J, O'Riain C, Tan K, Marzec J, Araf S, Wang J, Lee AM et al.. (2013) EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood122 (18): 3165-8. [PMID:24052547]

4. Campbell JE, Kuntz KW, Knutson SK, Warholic NM, Keilhack H, Wigle TJ, Raimondi A, Klaus CR, Rioux N, Yokoi A et al.. (2015) EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity. ACS Med Chem Lett6 (5): 491-5. [PMID:26005520]

5. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y. (2002) Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science298 (5595): 1039-43. [PMID:12351676]

6. Diaz E, Machutta CA, Chen S, Jiang Y, Nixon C, Hofmann G, Key D, Sweitzer S, Patel M, Wu Z et al.. (2012) Development and validation of reagents and assays for EZH2 peptide and nucleosome high-throughput screens. J Biomol Screen17 (10): 1279-92. [PMID:22904200]

7. Karantanos T, Chistofides A, Barhdan K, Li L, Boussiotis VA. (2016) Regulation of T Cell Differentiation and Function by EZH2. Front Immunol7: 172. [PMID:27199994]

8. Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Porter Scott M, Chesworth R, Moyer MP, Copeland RA et al.. (2013) Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc. Natl. Acad. Sci. U.S.A.110 (19): 7922-7. [PMID:23620515]

9. Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, Sacks JD, Raimondi A, Majer CR, Song J et al.. (2012) A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol.8 (11): 890-6. [PMID:23023262]

10. Konze KD, Ma A, Li F, Barsyte-Lovejoy D, Parton T, Macnevin CJ, Liu F, Gao C, Huang XP, Kuznetsova E et al.. (2013) An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS Chem. Biol.8 (6): 1324-34. [PMID:23614352]

11. Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D. (2002) Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev.16 (22): 2893-905. [PMID:12435631]

12. Margueron R, Li G, Sarma K, Blais A, Zavadil J, Woodcock CL, Dynlacht BD, Reinberg D. (2008) Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol. Cell32 (4): 503-18. [PMID:19026781]

13. Margueron R, Reinberg D. (2011) The Polycomb complex PRC2 and its mark in life. Nature469 (7330): 343-9. [PMID:21248841]

14. Martin C, Zhang Y. (2005) The diverse functions of histone lysine methylation. Nat. Rev. Mol. Cell Biol.6 (11): 838-49. [PMID:16261189]

15. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Della Pietra 3rd A, Diaz E et al.. (2012) EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature492 (7427): 108-12. [PMID:23051747]

16. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, Paul JE, Boyle M, Woolcock BW, Kuchenbauer F et al.. (2010) Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet.42 (2): 181-5. [PMID:20081860]

17. Qi W, Chan H, Teng L, Li L, Chuai S, Zhang R, Zeng J, Li M, Fan H, Lin Y et al.. (2012) Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc. Natl. Acad. Sci. U.S.A.109 (52): 21360-5. [PMID:23236167]

18. Shen X, Liu Y, Hsu YJ, Fujiwara Y, Kim J, Mao X, Yuan GC, Orkin SH. (2008) EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol. Cell32 (4): 491-502. [PMID:19026780]

19. Shiogama S, Yoshiba S, Soga D, Motohashi H, Shintani S. (2013) Aberrant expression of EZH2 is associated with pathological findings and P53 alteration. Anticancer Res.33 (10): 4309-17. [PMID:24122997]

20. Simon JA, Kingston RE. (2009) Mechanisms of polycomb gene silencing: knowns and unknowns. Nat. Rev. Mol. Cell Biol.10 (10): 697-708. [PMID:19738629]

21. Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, Copeland RA. (2010) Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl. Acad. Sci. U.S.A.107 (49): 20980-5. [PMID:21078963]

22. Souroullas GP, Jeck WR, Parker JS, Simon JM, Liu JY, Paulk J, Xiong J, Clark KS, Fedoriw Y, Qi J et al.. (2016) An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat. Med.22 (6): 632-40. [PMID:27135738]

23. Tsou PS, Coit P, Kilian NC, Sawalha AH. (2017) EZH2 modulates the DNA methylome and controls T cell adhesion through junctional adhesion molecule-A in lupus patients. Arthritis Rheumatol,  [Epub ahead of print]. [PMID:28973837]

24. Vaswani RG, Gehling VS, Dakin LA, Cook AS, Nasveschuk CG, Duplessis M, Iyer P, Balasubramanian S, Zhao F, Good AC et al.. (2016) Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas. J. Med. Chem.,  [Epub ahead of print]. [PMID:27739677]

25. Verma SK, Tian X, LaFrance LV, Duquenne C, Suarez DP, Newlander KA, Romeril SP, Burgess JL, Grant SW, Brackley JA et al.. (2012) Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2. ACS Med Chem Lett3 (12): 1091-6. [PMID:24900432]

26. Zhao E, Maj T, Kryczek I, Li W, Wu K, Zhao L, Wei S, Crespo J, Wan S, Vatan L et al.. (2016) Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat. Immunol.17 (1): 95-103. [PMID:26523864]

How to cite this page

2.1.1.43 Histone methyltransferases (HMTs): enhancer of zeste 2 polycomb repressive complex 2 subunit. Last modified on 11/10/2017. Accessed on 14/12/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2654.