The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type

Yemin Wang, Shary Yuting Chen, Anthony Karnezis, Shane Colborne, Nancy Dos Santos, Jessica D. Lang, William P.D. Hendricks, Krystal A. Orlando, Damian Yap, Friedrich Kommoss, Marcel B. Bally, Gregg B. Morin, Jeffrey M. Trent, Bernard E. Weissman, David G. Huntsman

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Small cell carcinoma of the ovary, hypercalcaemic 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-remodelling 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-remodelling 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 tumour 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. EZH2 inhibitors suppressed tumour 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.

Original languageEnglish (US)
Pages (from-to)371-383
Number of pages13
JournalJournal of Pathology
Volume242
Issue number3
DOIs
StatePublished - Jul 1 2017
Externally publishedYes

Fingerprint

Small Cell Carcinoma
Ovary
Therapeutics
Chromatin Assembly and Disassembly
Genes
histone methyltransferase
Apoptosis
Neoplasms
Cell Cycle Checkpoints
Heterografts
Epigenomics
Adenosine Triphosphatases
Cell Differentiation
Cell Cycle
Hypersensitivity
Immunohistochemistry
Genome
Pharmacology
Neurons
Cell Line

Keywords

  • chromatin remodelling complex
  • differentiation
  • EZH2
  • ovarian cancer
  • SCCOHT
  • SMARCA4
  • SWI/SNF

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type. / Wang, Yemin; Chen, Shary Yuting; Karnezis, Anthony; Colborne, Shane; Santos, Nancy Dos; Lang, Jessica D.; Hendricks, William P.D.; Orlando, Krystal A.; Yap, Damian; Kommoss, Friedrich; Bally, Marcel B.; Morin, Gregg B.; Trent, Jeffrey M.; Weissman, Bernard E.; Huntsman, David G.

In: Journal of Pathology, Vol. 242, No. 3, 01.07.2017, p. 371-383.

Research output: Contribution to journalArticle

Wang, Y, Chen, SY, Karnezis, A, Colborne, S, Santos, ND, Lang, JD, Hendricks, WPD, Orlando, KA, Yap, D, Kommoss, F, Bally, MB, Morin, GB, Trent, JM, Weissman, BE & Huntsman, DG 2017, 'The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type', Journal of Pathology, vol. 242, no. 3, pp. 371-383. https://doi.org/10.1002/path.4912
Wang, Yemin ; Chen, Shary Yuting ; Karnezis, Anthony ; Colborne, Shane ; Santos, Nancy Dos ; Lang, Jessica D. ; Hendricks, William P.D. ; Orlando, Krystal A. ; Yap, Damian ; Kommoss, Friedrich ; Bally, Marcel B. ; Morin, Gregg B. ; Trent, Jeffrey M. ; Weissman, Bernard E. ; Huntsman, David G. / The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type. In: Journal of Pathology. 2017 ; Vol. 242, No. 3. pp. 371-383.
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abstract = "Small cell carcinoma of the ovary, hypercalcaemic 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-remodelling 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-remodelling 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 tumour 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. EZH2 inhibitors suppressed tumour 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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AU - Weissman, Bernard E.

AU - Huntsman, David G.

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