Targeting EZH2-mediated methylation of H3K27 inhibits proliferation and migration of Synovial Sarcoma in vitro

Synovial sarcoma is an aggressive soft tissue sarcoma genetically defined by the fusion oncogene SS18-SSX. It is hypothesized that either SS18-SSX disrupts SWI/SNF complex inhibition of the polycomb complex 2 (PRC2) methyltransferase Enhancer of Zeste Homologue 2 (EZH2), or that SS18-SSX is able to...

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Bibliographic Details
Published in:Scientific reports 2016-04, Vol.6 (1), p.25239-25239, Article 25239
Main Authors: Shen, Jacson K., Cote, Gregory M., Gao, Yan, Choy, Edwin, Mankin, Henry J., Hornicek, Francis J., Duan, Zhenfeng
Format: Article
Language:English
Subjects:
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Cell growth
Cell Line, Tumor
Cell Movement
Cell Proliferation
Clinical trials
Enhancer of Zeste Homolog 2 Protein - metabolism
Gene Knockdown Techniques
Gene silencing
Histones - metabolism
Humanities and Social Sciences
Humans
Lysine - metabolism
Methylation
Methyltransferase
multidisciplinary
Polycomb group proteins
Protein Processing, Post-Translational
Sarcoma
Sarcoma, Synovial - pathology
Science
siRNA
Soft tissue sarcoma
SWI/SNF complex
Synovial sarcoma
Tumor cell lines
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Summary:Synovial sarcoma is an aggressive soft tissue sarcoma genetically defined by the fusion oncogene SS18-SSX. It is hypothesized that either SS18-SSX disrupts SWI/SNF complex inhibition of the polycomb complex 2 (PRC2) methyltransferase Enhancer of Zeste Homologue 2 (EZH2), or that SS18-SSX is able to directly recruit PRC2 to aberrantly silence target genes. This is of potential therapeutic value as several EZH2 small molecule inhibitors are entering early phase clinical trials. In this study, we first confirmed EZH2 expression in the 76% of human synovial sarcoma samples. We subsequently investigated EZH2 as a therapeutic target in synovial sarcoma in vitro . Knockdown of EZH2 by shRNA or siRNA resulted in inhibition of cell growth and migration across a series of synovial sarcoma cell lines. The EZH2 selective small-molecule inhibitor EPZ005687 similarly suppressed cell proliferation and migration. These data support the hypothesis that targeting EZH2 may be a promising therapeutic strategy in the treatment of synovial sarcoma; clinical trials are initiating enrollment currently.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep25239