Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma.
The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multi...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4938529?pdf=render |
| _version_ | 1811322522502692864 |
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| author | Satoshi Kawano Alexandra R Grassian Masumi Tsuda Sarah K Knutson Natalie M Warholic Galina Kuznetsov Shanqin Xu Yonghong Xiao Roy M Pollock Jesse S Smith Kevin K Kuntz Scott Ribich Yukinori Minoshima Junji Matsui Robert A Copeland Shinya Tanaka Heike Keilhack |
| author_facet | Satoshi Kawano Alexandra R Grassian Masumi Tsuda Sarah K Knutson Natalie M Warholic Galina Kuznetsov Shanqin Xu Yonghong Xiao Roy M Pollock Jesse S Smith Kevin K Kuntz Scott Ribich Yukinori Minoshima Junji Matsui Robert A Copeland Shinya Tanaka Heike Keilhack |
| author_sort | Satoshi Kawano |
| collection | DOAJ |
| description | The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2) methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1) has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma-a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein-display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinical-stage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers. |
| first_indexed | 2024-04-13T13:36:31Z |
| format | Article |
| id | doaj.art-056beb7617a242fcb7ff5a42aa85f783 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T13:36:31Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-056beb7617a242fcb7ff5a42aa85f7832022-12-22T02:44:45ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01117e015888810.1371/journal.pone.0158888Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma.Satoshi KawanoAlexandra R GrassianMasumi TsudaSarah K KnutsonNatalie M WarholicGalina KuznetsovShanqin XuYonghong XiaoRoy M PollockJesse S SmithKevin K KuntzScott RibichYukinori MinoshimaJunji MatsuiRobert A CopelandShinya TanakaHeike KeilhackThe catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2) methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1) has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma-a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein-display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinical-stage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers.http://europepmc.org/articles/PMC4938529?pdf=render |
| spellingShingle | Satoshi Kawano Alexandra R Grassian Masumi Tsuda Sarah K Knutson Natalie M Warholic Galina Kuznetsov Shanqin Xu Yonghong Xiao Roy M Pollock Jesse S Smith Kevin K Kuntz Scott Ribich Yukinori Minoshima Junji Matsui Robert A Copeland Shinya Tanaka Heike Keilhack Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma. PLoS ONE |
| title | Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma. |
| title_full | Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma. |
| title_fullStr | Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma. |
| title_full_unstemmed | Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma. |
| title_short | Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma. |
| title_sort | preclinical evidence of anti tumor activity induced by ezh2 inhibition in human models of synovial sarcoma |
| url | http://europepmc.org/articles/PMC4938529?pdf=render |
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