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Richter, G.H.S.* ; Plehm, S.* ; Fasan, A.* ; Rössler, S.* ; Unland, R.* ; Bennani-Baiti, I.M.* ; Hotfilder, M.* ; Löwel, D.* ; von Luettichau, I.* ; Mossbrugger, I. ; Quintanilla-Martinez, L. ; Kovar, H.* ; Staege, M.S.* ; Müller-Tidow, C.* ; Burdach, S.*

EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation.

Proc. Natl. Acad. Sci. U.S.A. 106, 5324-5329 (2009)
DOI PMC
Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
Ewing tumors (ET) are highly malignant, localized in bone or soft tissue, and are molecularly defined by ews/ets translocations. DNA microarray analysis revealed a relationship of ET to both endothelium and fetal neural crest. We identified expression of histone methyltransferase enhancer of Zeste, Drosophila, Homolog 2 (EZH2) to be increased in ET. Suppressive activity of EZH2 maintains sternness in normal and malignant cells. Here, we found EWS/FLI1 bound to the EZH2 promoter in vivo, and induced EZH2 expression in ET and mesenchymal stem cells. Down-regulation of EZH2 by RNA interference in ET suppressed oncogenic transformation by inhibiting clonogenicity in vitro. Similarly, tumor development and metastasis was suppressed in immunodeficient Rag2(-/-)gamma c(-/-) mice. EZH2-mediated gene silencing was shown to be dependent on histone deacetylase (HDAC) activity. Subsequent microarray analysis of EZH2 knock down, HDAC-inhibitor treatment and confirmation in independent assays revealed an undifferentiated phenotype maintained by EZH2 in ET. EZH2 regulated sternness genes such as nerve growth factor receptor (NGFR), as well as genes involved in neuroectodermal and endothelial differentiation (EMP1, EPHB2, GFAP, and GAP43). These data suggest that EZH2 might have a central role in ET pathology by shaping the oncogenicity and stem cell phenotype of this tumor.
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Publication type Article: Journal article
Document type Scientific Article
Keywords epigenetic regulation; Ewing tumor; stemness; mesenchymal progenitor cells; group protein ezh2; stem-cell; dna methylation; ewings-sarcoma; transcriptional modulation; cluster-analysis; gene-expression; cancer; genome
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 106, Issue: 13, Pages: 5324-5329 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Reviewing status Peer reviewed
Institute(s) Institute of Pathology (PATH)