Browse > Article
http://dx.doi.org/10.5483/BMBRep.2022.55.12.174

The role of EZH1 and EZH2 in development and cancer  

Soo Hyun, Lee (Department of Biomedical Sciences, Seoul National University College of Medicine)
Yingying, Li (Department of Biomedical Sciences, Seoul National University College of Medicine)
Hanbyeol, Kim (Department of Biomedical Sciences, Seoul National University College of Medicine)
Seounghyun, Eum (Department of Biomedical Sciences, Seoul National University College of Medicine)
Kyumin, Park (Department of Biomedical Sciences, Seoul National University College of Medicine)
Chul-Hwan, Lee (Department of Biomedical Sciences, Seoul National University College of Medicine)
Publication Information
BMB Reports / v.55, no.12, 2022 , pp. 595-601 More about this Journal
Abstract
Polycomb Repressive Complex 2 (PRC2) exhibits key roles in mammalian development through its temporospatial repression of gene expression. EZH1 or EZH2 is the catalytic subunit of PRC2 that mediates the mono-, di- and tri-methylation of histone H3 lysine 27 (H3K27me1/2/3), H3K27me2/me3 being a hallmark of facultative heterochromatin. PRC2 is a chromatin-modifying enzyme that is recruited to a limited number of "nucleation sites", spreads H3K27 methylation and fosters chromatin compaction. EZH1 and EZH2 exhibit differences in their expression patterns, levels of histone methyltransferase activity (HMT) in the context of PRC2, and DNA/nucleosome binding activity. This suggests that their roles in heterochromatin formation are disparate. Dysregulation of PRC2 activity leads to aberrant gene expression and is implicated in cancer and developmental diseases. In this review, we discuss the distinct function of PRC2/EZH1 and PRC2/EZH2 in the early and late developmental stages. We then discuss the cancers associated with PRC2/EZH1 and PRC2/EZH2.
Keywords
Cancer; Development; Epigenetics; EZH1/2; Heterochromatin; PRC2;
Citations & Related Records
Times Cited By KSCI : 5  (Citation Analysis)
연도 인용수 순위
1 Yuan W, Wu T, Fu H et al (2012) Dense chromatin activates polycomb repressive complex 2 to regulate H3 lysine 27 methylation. Science 337, 971-975   DOI
2 Bratkowski M, Yang X and Liu X (2018) An evolutionarily conserved structural platform for PRC2 inhibition by a class of Ezh2 inhibitors. Sci Rep 8, 9092
3 Bracken AP, Pasini D, Capra M, Prosperini E, Colli E and Helin K (2003) EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J 22, 5323-5335   DOI
4 Von Schimmelmann M, Feinberg PA, Sullivan JM et al (2016) Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration HHS public access. Nat Neurosci 19, 1321-1330   DOI
5 Shen X, Liu Y, Hsu YJ et al (2008) EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell 32, 491-502   DOI
6 Lavarone E, Barbieri CM and Pasini D (2019) Dissecting the role of H3K27 acetylation and methylation in PRC2 mediated control of cellular identity. Nat Commun 10, 1-16   DOI
7 Jadhav U, Manieri E, Nalapareddy K et al (2020) Replicational dilution of H3K27me3 in mammalian cells and the role of poised promoters. Mol Cell 78, 141-151   DOI
8 He A, Ma Q, Cao J et al (2012) Polycomb repressive complex 2 regulates normal development of the mouse heart. Circ Res 110, 406-415   DOI
9 Ezhkova E, Pasolli HA, Parker JS et al (2009) Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell 136, 1122-1135   DOI
10 Ezhkova E, Lien W-H, Stokes N, Pasolli HA, Silva JM and Fuchs E (2011) EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair. Genes Dev 25, 485-498   DOI
11 Hidalgo I, Herrera-Merchan A, Ligos JM et al (2012) Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest. Cell Stem Cell 11, 649-662
12 von Schimmelmann M, Feinberg PA, Sullivan JM et al (2016) Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration. Nat Neurosci 2, 1-14   DOI
13 Vo LT, Kinney MA, Liu X et al (2018) Regulation of embryonic haematopoietic multipotency by EZH1. Nature 553, 506-510   DOI
14 Ai S, Yu X, Li Y et al (2017) Divergent requirements for EZH1 in heart development versus regeneration. Circ Res 121, 106-112   DOI
15 Hoy SM (2020) Tazemetostat: first approval. Drugs 80, 513-521   DOI
16 Chen Z, Yang P, Li W et al (2018) Expression of EZH2 is associated with poor outcome in colorectal cancer. Oncol Lett 15, 2953-2961
17 Huet S, Xerri L, Tesson B et al (2017) EZH2 alterations in follicular lymphoma: biological and clinical correlations. Blood Cancer J 7, e555
18 Varambally S, Dhanasekaran SM, Zhou M et al (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624-629   DOI
19 Zingg D, Debbache J, Schaefer SM et al (2015) The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors. Nat Commun 6, 6051
20 Takata K, Miyata-Takata T, Sato Y and Yoshino T (2014) Pathology of follicular lymphoma. J Clin Exp Hematop 54, 3-9   DOI
21 Bodor C, Grossmann V, Popov N et al (2013) EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood 122, 3165-3168
22 Yap DB, Chu J, Berg T et al (2011) Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 117, 2451-2459   DOI
23 McCabe MT, Graves AP, Ganji G et al (2012) Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci 109, 2989-2994   DOI
24 Ott HM, Graves AP, Pappalardi MB et al (2014) A687V EZH2 is a driver of histone H3 lysine 27 (H3K27) hypertrimethylation. Mol Cancer Ther 13, 3062-3073   DOI
25 Souroullas GP, Jeck WR, Parker JS et al (2016) An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med 22, 632-640
26 Becker PB and Workman JL (2013) Nucleosome remodeling and epigenetics. Cold Spring Harb Perspect Biol 5, a017905
27 Euskirchen G, Auerbach RK and Snyder M (2012) SWI/SNF chromatin-remodeling factors: multiscale analyses and diverse functions. J Biol Chem 287, 30897-30905   DOI
28 Kadoch C, Williams RT Calarco JP et al (2017) Dynamics of BAF-Polycomb complex opposition on heterochromatin in normal and oncogenic states. Nat Genet 49, 213-222   DOI
29 Zhang W, Chronis C, Chen X et al (2019) The BAF and PRC2 complex subunits dpf2 and eed antagonistically converge on Tbx3 to control ESC differentiation. Cell Stem Cell 24, 138-152
30 Schuettengruber B, Bourbon HM, Di Croce L and Cavalli G (2017) Genome regulation by polycomb and trithorax: 70 years and counting. Cell 171, 34-57   DOI
31 Wilson BG, Wang X, Shen X et al (2010) Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18, 316-328   DOI
32 Song YS and Park YJ (2019) Genomic characterization of differentiated thyroid carcinoma. Endocrinol Metab 34, 1-10   DOI
33 Mittal P, and Roberts CWM (2020) The SWI/SNF complex in cancer - biology, biomarkers and therapy. Nat Rev Clin Oncol 17, 435-448   DOI
34 Weber CM, Hafner A, Kirkland JG et al (2021) mSWI/SNF promotes polycomb repression both directly and through genome-wide redistribution. Nat Struct Mol Biol 28, 501-511   DOI
35 Calebiro D, Grassi ES, Eszlinger M et al (2016) Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas. J Clin Invest 126, 3383-3388   DOI
36 Jung CK, Kim Y, Jeon S, Jo K, Lee S and Bae JS (2018) Clinical utility of EZH1 mutations in the diagnosis of follicular-patterned thyroid tumors. Hum Pathol 81, 9-17   DOI
37 Poepsel S, Kasinath V and Nogales E (2018) Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes. Nat Struct Mol 25, 154-162   DOI
38 Chen S, Jiao L, Shubbar M, Yang X and Liu X (2018) Unique structural platforms of Suz12 dictate distinct classes of PRC2 for chromatin binding. Mol Cell 69, 802-819   DOI
39 Yu JR, Lee CH, Oksuz O, Stafford JM and Reinberg D (2019) PRC2 is high maintenance. Genes Dev 33, 903-905   DOI
40 Margueron R and Reinberg D (2011) The polycomb complex PRC2 and its mark in life. Nature 469, 343-349   DOI
41 Margueron R, Justin N, Ohno K et al (2009) Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461, 762-767   DOI
42 Cao R, Wang L, Wang H et al (2002) Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science 298, 1039-1043   DOI
43 Czermin B, Melfi R, McCabe D, Seitz V, Imhof A and Pirrotta V (2002) Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 111, 185-196   DOI
44 Hansen KH, Bracken AP, Pasini D et al (2008) A model for transmission of the H3K27me3 epigenetic mark. Nat Cell Biol 10, 1291-1300
45 Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P and Reinberg D (2002) Histone methyltransferase activity associated with a human multiprotein complex containing the enhancer of zeste protein. Genes Dev 16, 2893-2905   DOI
46 Justin N, Zhang Y, Tarricone C et al (2016) Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2. Nat Commun 7, 11316
47 Lee CH, Yu JR, Kumar S et al (2018) Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin. Mol Cell 70, 422-434   DOI
48 Oksuz O, Narendra V, Lee CH et al(2018) Capturing the onset of PRC2-mediated repressive domain formation. Mol Cell 70, 1149-1162   DOI
49 Cao R and Zhang Y (2004) SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell 15, 57-67   DOI
50 Schmitges FW, Prusty AB, Faty M et al (2011) Histone methylation by PRC2 is inhibited by active chromatin marks. Mol Cell 42, 330-341   DOI
51 Chammas P, Mocavini I and Di Croce L (2020) Engaging chromatin: PRC2 structure meets function. Br J Cancer 122, 315-328
52 Glancy E, Ciferri C and Bracken AP (2021) Structural basis for PRC2 engagement with chromatin. Curr Opin Struct Biol 67, 135-144   DOI
53 Piunti A, Smith ER, Morgan MAJ et al (2019) Catacomb: an endogenous inducible gene that antagonizes H3K27 methylation activity of polycomb repressive complex 2 via an H3K27M-like mechanism. Sci Adv 5, eaax2887
54 Beringer M, Pisano P, Di Carlo V et al (2016) EPOP functionally links elongin and polycomb in pluripotent stem cells. Mol Cell 64, 645-658   DOI
55 Ragazzini R, Perez-Palacios R, Baymaz IH et al (2019) EZHIP constrains polycomb repressive complex 2 activity in germ cells. Nat Commun 10, 3858
56 Conway E, Jerman E, Healy E et al (2018) A family of vertebrate-specific polycombs encoded by the LCOR/LCORL genes balance PRC2 subtype activities. Mol Cell 70, 408-421   DOI
57 Liefke R, Karwacki-Neisius V, Shi Y et al (2016) EPOP interacts with elongin BC and USP7 to modulate the chromatin landscape. Mol Cell 64, 659-672   DOI
58 Hojfeldt JW, Hedehus L, Laugesen A, Tatar T, Wiehle L and Helin K (2019) Non-core subunits of the PRC2 complex are collectively required for its target-site specificity. Mol Cell 76, 423-436   DOI
59 Laugesen A, Hojfeldt JW and Helin K (2019) Molecular mechanisms directing PRC2 recruitment and H3K27 methylation. Mol Cell 74, 8-18   DOI
60 Lee CH, Holder M, Grau D et al (2018) Distinct stimulatory mechanisms regulate the catalytic activity of polycomb repressive complex 2. Mol Cell 70, 435-448   DOI
61 Son J, Shen SS, Margueron R and Reinberg D (2013) Nucleosome-binding activities within JARID2 and EZH1 regulate the function of PRC2 on chromatin. Genes Dev 27, 2663-2677   DOI
62 Margueron R, Li G, Sarma K et al (2008) Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell 32, 503-518   DOI
63 Grau D, Zhang Y, Lee CH et al (2021) Structures of monomeric and dimeric PRC2:EZH1 reveal flexible modules involved in chromatin compaction. Nat Commun 12, 714