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The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcemic type Wang, Yemin; Chen, Shary Yuting; Karnezis, Anthony N.; Colborne, Shane; Santos, Nancy; Lang, Jessica; Hendricks, William P. D.; Orlando, Krystal; Yap, Damian; Kommoss, Friedrich; et al.
Abstract
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but aggressive and untreatable malignancy affecting young women. We and others recently discovered that SMARCA4, a gene encoding the ATPase of the SWI/SNF chromatin-remodeling complex, is the only gene recurrently mutated in the majority of SCCOHT. The low somatic complexity of SCCOHT genomes and the prominent role of the SWI/SNF chromatin-remodeling complex in transcriptional control of genes suggest that SCCOHT cells may rely on epigenetic rewiring for oncogenic transformation. Herein, we report that approximately 80% (19/24) of SCCOHT tumor samples have strong expression of the histone methyltransferase EZH2 by immunohistochemistry with the rest expressing variable amounts of EZH2. Re-expression of SMARCA4 suppressed the expression of EZH2 in SCCOHT cells. In comparison to other ovarian cell lines, SCCOHT cells displayed hypersensitivity to EZH2 shRNAs and two selective EZH2 inhibitors, GSK126 and EPZ-6438. EZH2 inhibitors induced cell cycle arrest, apoptosis, and cell differentiation in SCCOHT cells, along with the induction of genes involved in cell cycle regulation, apoptosis and neuron-like differentiation. EPZ-6438 suppressed tumor growth and improved the survival of mice bearing SCCOHT xenografts. Therefore, our data suggest that loss of SMARCA4 creates a dependency on the catalytic activity of EZH2 in SCCOHT cells and that pharmacological inhibition of EZH2 is a promising therapeutic strategy for treating this disease.
Item Metadata
Title |
The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcemic type
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Alternate Title |
Targeting EZH2 in SCCOHT
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Creator |
Wang, Yemin; Chen, Shary Yuting; Karnezis, Anthony N.; Colborne, Shane; Santos, Nancy; Lang, Jessica; Hendricks, William P. D.; Orlando, Krystal; Yap, Damian; Kommoss, Friedrich; Bally, Marcel B., 1956-; Morin, Gregg B.; Hunstman, David G.; Trent, Jeffrey M.; Weissman, Bernard E.; Hunstman, David G.
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Date Issued |
2017-04
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Description |
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but aggressive and
untreatable malignancy affecting young women. We and others recently discovered that
SMARCA4, a gene encoding the ATPase of the SWI/SNF chromatin-remodeling complex, is the
only gene recurrently mutated in the majority of SCCOHT. The low somatic complexity of
SCCOHT genomes and the prominent role of the SWI/SNF chromatin-remodeling complex in
transcriptional control of genes suggest that SCCOHT cells may rely on epigenetic rewiring for
oncogenic transformation. Herein, we report that approximately 80% (19/24) of SCCOHT tumor
samples have strong expression of the histone methyltransferase EZH2 by immunohistochemistry
with the rest expressing variable amounts of EZH2. Re-expression of SMARCA4 suppressed the
expression of EZH2 in SCCOHT cells. In comparison to other ovarian cell lines, SCCOHT cells
displayed hypersensitivity to EZH2 shRNAs and two selective EZH2 inhibitors, GSK126 and
EPZ-6438. EZH2 inhibitors induced cell cycle arrest, apoptosis, and cell differentiation in
SCCOHT cells, along with the induction of genes involved in cell cycle regulation, apoptosis and
neuron-like differentiation. EPZ-6438 suppressed tumor growth and improved the survival of
mice bearing SCCOHT xenografts. Therefore, our data suggest that loss of SMARCA4 creates a
dependency on the catalytic activity of EZH2 in SCCOHT cells and that pharmacological
inhibition of EZH2 is a promising therapeutic strategy for treating this disease.
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Subject | |
Genre | |
Type | |
Language |
eng
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Date Available |
2018-10-01
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0347334
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URI | |
Affiliation | |
Publisher DOI |
10.1002/path.4912
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Peer Review Status |
Reviewed
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Scholarly Level |
Faculty; Researcher
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International