pISSN 1907-3062 | eISSN 2407-2230 | Universa Medicina content is searchable on DOAJ, Google Scholar, and OAI

Enhancer of zeste homolog 2 regulates cell differentiation and proliferation in neuroblastoma

Amallia N. Setyawati, Takehiko Kamijo
Submission date: Monday, 30 November 2015
Published date: Tuesday, 02 December 2014
DOI: http://dx.doi.org/10.18051/UnivMed.2014.v33.153-162

Article Metrics

Abstract viewed: 219 times



Neuroblastoma  (NB)  is  one  of  the  most  common  extracranial  solid  tumors

occurring in infancy and childhood with highly variable outcomes. Polycomb

group (PcG) proteins are epigenetic gene silencers. Enhancer of zeste homolog

2 (EZH2) is a member of the polycomb repressor complex 2 (PRC2) group,

with  the  main  function  to  catalyze  the  polycomb  repressor  complex  by

methylating lysine 9 and 27 of histone H3. This study aimed to investigate the

biological functionality of EZH2 in NB.



This was an experimental study with an analysis of correlation initially of the

known prognostic factors of NB patients’ outcomes, by comparing the expression

of v-myc avian myelocytomatosis viral oncogene neuroblastoma (MYCN) with

that of EZH2, on the basis of the patients’ overall and relapse free survival

rates. This was followed with a biological functional study to assess the role of

EZH2 expression in NB.



EZH2 knockdown induces neurite extension and differentiation marker growth

associated  protein  43  (GAP43)  in  NB  cells,  although  it  does  not  affect  cell

cycle. By ectopic expression of EZH2, all-trans retinoic acid (ATRA) inducedneurite extension was suppressed and GAP43 was decreased. Overall, EZH2

seems to have an important role in NB cell differentiation. Although EZH2 did

not alter cell proliferation, in the soft agar colony formation assay there was a

significant increase in total colony number and number of large colonies.



Our  result  clarified  the  potential  role  of  EZH2  in  the  regulation  of  cell

differentiation and proliferation, which subsequently may play an important

role in the poor prognosis of NB patients.


Neuroblastoma; EZH2; MYCN

Full Text:



Paffhausen T, Schwab M, Westermann F. Targeted MYCN expression affects cytotoxic potential of chemotherapeutic drugs in neuroblastoma cells. Cancer Lett 2007;250:17-24.

Weber A, Starke S, Bergmann E, Christiansen H. The coamplification pattern of the MYCN amplicon is an invariable attribute of most MYCN-amplified human neuroblastomas. Clin

Cancer Res 2006;12:7316-21.

Rajasekhar VK, Begemann M. Concise review: roles of polycomb group proteins in development and disease: a stem cell perspective. Stem Cells 2007;25:2498–510.

Esteller M. Cancer epigenomics: DNA methylomes and histone modification maps. Nat Rev Genet 2007;8:286–98.

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-74.

Schwartz YB, Pirrotta V. Polycomb complexes and epigenetic states. Curr Opin Cell Biol 2008;20:266–73

Ochiai H, Takenobu H, Nakagawa A, Yamaguchi Y, Kimura M, Ohira M, et al. Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1Bbeta and TSLC1 in

neuroblastoma. Oncogene 2010;6;29:2681-90.

Kamijo T. Role of stemness-related molecules in neuroblastoma. Pediatr Res 2012;71:511–5.

Sauvageau M, Sauvageau G. Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell 2010;7:299-31.

Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH, et al. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer Cell 2011;19:86-100.

Piunti A, Pasini D. Epigenetic factors in cancer development: polycomb group proteins. Future Oncol 2011;7:57-75.

Kurata K, Yanagisawa R, Ohira M, Kitagawa M, Nakagawara A, Kamijo T. Stress via p53 pathway causes apoptosis by mitochondrial Noxa upregulation in doxorubicin-treated neuroblastoma cells. Oncogene 2008;27:741-54.

de Napoles M, Mermoud JE, Wakao R, Tang YA, Endoh M, Appanah R, et al. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X

inactivation. Dev Cell 2004;7:663-76.

Wang C, Liu Z, Woo CW, Li Z, Wang L, Wei JS, et al. EZH2 mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3, and NGFR. Cancer Res 2012;72:315-

Pereira JD, Sansom SN, Smith J, Dobenecker MW, Tarakhovsky A, Livesey FJ. Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc Natl Acad Sci USA


Sher F, Rossler R, Brouwer N, Balasubramaniyan V, Boddeke E, Copray S. Differentiation of neural stem cells into oligodendrocytes: involvement of the polycomb group protein Ezh2. Stem Cells 2008;26:2875–83.

Sher F, Boddeke E, Olah M, Copray S. Dynamic changes in Ezh2 gene occupancy underlie its involvement in neural stem cell self-renewal and differentiation towards oligodendrocytes. PLoS

One 2012;7:e40399.

Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report.

J Clin Oncol 2009;27:289-97.

Kidney G, S Baritaki, Marathe H, Feng J, Park S, Beach S, et al. Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in

breast and prostate cancer. Cancer Res 2012;72:309-104.

Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani RS, Tomlins SA, et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 2008;27:7274-84.

Richter GH, Plehm S, Fasan A, Rossler S, Unland R, Bennani-Baiti IM, et al. EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuroectodermal differentiation. Proc Natl Acad Sci USA 2009;06:5324-9.

Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH, et al. Epigenetic mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastomainitiating

cells. Cancer Cell 2008;13:69-80

McHugh JB, Fullen RD, Ma L, Kleer CG, Su LD. Expression of polycomb group protein EZH2 in nevi and melanoma. J Cutan Pathol 2007;34:597-600.

Rajasekhar VK, Dalerba P, Passegue E, Lagasse E, Najbauer J. Stem cells, cancer, and context dependence. Stem Cells 2007;26:292-8.

Vire E, Brenner C, Deplus R, Blanchon L, Frage M, Didetot C, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006;439:871–4.

Keshet I, Schlesinger Y, Farkash S, Rand E, Hecht M, Segal E, Pikarski E, et al. Evidence for an instructive mechanism of de novo methylation in cancer cells. Nat Genet 2006;38:149–53.

Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, et al. Polycombmediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 2007;39:232–6.


  • There are currently no refbacks.

Copyright (c) 2014 Amallia N. Setyawati, Takehiko Kamijo

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Creative Commons License
Universa Medicina by Faculty of Medicine, Trisakti University is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Based on a work at https://univmed.org/ejurnal/index.php/medicina/