Histone deacetylase inhibitors synergize with catalytic inhibitors of EZH2 to exhibit antitumor activity in small cell carcinoma of the ovary, hypercalcemic type

Yemin Wang, Shary Yuting Chen, Shane Colborne, Galen Lambert, Chae Young Shin, Nancy Dos Santos, Krystal A. Orlando, Jessica D. Lang, William P.D. Hendricks, Marcel B. Bally, Anthony Karnezis, Ralf Hass, T. Michael Underhill, Gregg B. Morin, Jeffrey M. Trent, Bernard E. Weissman, David G. Huntsman

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but extremely lethal malignancy that mainly impacts young women. SCCOHT is characterized by a diploid genome with loss of SMARCA4 and lack of SMARCA2 expression, two mutually exclusive ATPases of the SWI/SNF chromatin-remodeling complex. We and others have identified the histone methyltransferase EZH2 as a promising therapeutic target for SCCOHT, suggesting that SCCOHT cells depend on the alternation of epigenetic pathways for survival. In this study, we found that SCCOHT cells were more sensitive to pan-HDAC inhibitors compared with other ovarian cancer lines or immortalized cell lines tested. Pan-HDAC inhibitors, such as quisinostat, reversed the expression of a group of proteins that were deregulated in SCCOHT cells due to SMARCA4 loss, leading to growth arrest, apoptosis, and differentiation in vitro and suppressed tumor growth of xenografted tumors of SCCOHT cells. Moreover, combined treatment of HDAC inhibitors and EZH2 inhibitors at sublethal doses synergistically induced histone H3K27 acetylation and target gene expression, leading to rapid induction of apoptosis and growth suppression of SCCOHT cells and xenografted tumors. Therefore, our preclinical study highlighted the therapeutic potential of combined treatment of HDAC inhibitors with EZH2 catalytic inhibitors to treat SCCOHT.

Original languageEnglish (US)
Pages (from-to)2767-2779
Number of pages13
JournalMolecular Cancer Therapeutics
Volume17
Issue number12
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

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Histone Deacetylase Inhibitors
Small Cell Carcinoma
Ovary
Neoplasms
Growth
Apoptosis
Chromatin Assembly and Disassembly
Therapeutics
Acetylation
Diploidy
Epigenomics
Ovarian Neoplasms
Histones
Adenosine Triphosphatases
Genome
Gene Expression
Cell Line
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Histone deacetylase inhibitors synergize with catalytic inhibitors of EZH2 to exhibit antitumor activity in small cell carcinoma of the ovary, hypercalcemic type. / Wang, Yemin; Chen, Shary Yuting; Colborne, Shane; Lambert, Galen; Shin, Chae Young; Santos, Nancy Dos; Orlando, Krystal A.; Lang, Jessica D.; Hendricks, William P.D.; Bally, Marcel B.; Karnezis, Anthony; Hass, Ralf; Underhill, T. Michael; Morin, Gregg B.; Trent, Jeffrey M.; Weissman, Bernard E.; Huntsman, David G.

In: Molecular Cancer Therapeutics, Vol. 17, No. 12, 01.12.2018, p. 2767-2779.

Research output: Contribution to journalArticle

Wang, Y, Chen, SY, Colborne, S, Lambert, G, Shin, CY, Santos, ND, Orlando, KA, Lang, JD, Hendricks, WPD, Bally, MB, Karnezis, A, Hass, R, Underhill, TM, Morin, GB, Trent, JM, Weissman, BE & Huntsman, DG 2018, 'Histone deacetylase inhibitors synergize with catalytic inhibitors of EZH2 to exhibit antitumor activity in small cell carcinoma of the ovary, hypercalcemic type', Molecular Cancer Therapeutics, vol. 17, no. 12, pp. 2767-2779. https://doi.org/10.1158/1535-7163.MCT-18-0348
Wang, Yemin ; Chen, Shary Yuting ; Colborne, Shane ; Lambert, Galen ; Shin, Chae Young ; Santos, Nancy Dos ; Orlando, Krystal A. ; Lang, Jessica D. ; Hendricks, William P.D. ; Bally, Marcel B. ; Karnezis, Anthony ; Hass, Ralf ; Underhill, T. Michael ; Morin, Gregg B. ; Trent, Jeffrey M. ; Weissman, Bernard E. ; Huntsman, David G. / Histone deacetylase inhibitors synergize with catalytic inhibitors of EZH2 to exhibit antitumor activity in small cell carcinoma of the ovary, hypercalcemic type. In: Molecular Cancer Therapeutics. 2018 ; Vol. 17, No. 12. pp. 2767-2779.
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abstract = "Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but extremely lethal malignancy that mainly impacts young women. SCCOHT is characterized by a diploid genome with loss of SMARCA4 and lack of SMARCA2 expression, two mutually exclusive ATPases of the SWI/SNF chromatin-remodeling complex. We and others have identified the histone methyltransferase EZH2 as a promising therapeutic target for SCCOHT, suggesting that SCCOHT cells depend on the alternation of epigenetic pathways for survival. In this study, we found that SCCOHT cells were more sensitive to pan-HDAC inhibitors compared with other ovarian cancer lines or immortalized cell lines tested. Pan-HDAC inhibitors, such as quisinostat, reversed the expression of a group of proteins that were deregulated in SCCOHT cells due to SMARCA4 loss, leading to growth arrest, apoptosis, and differentiation in vitro and suppressed tumor growth of xenografted tumors of SCCOHT cells. Moreover, combined treatment of HDAC inhibitors and EZH2 inhibitors at sublethal doses synergistically induced histone H3K27 acetylation and target gene expression, leading to rapid induction of apoptosis and growth suppression of SCCOHT cells and xenografted tumors. Therefore, our preclinical study highlighted the therapeutic potential of combined treatment of HDAC inhibitors with EZH2 catalytic inhibitors to treat SCCOHT.",
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AU - Wang, Yemin

AU - Chen, Shary Yuting

AU - Colborne, Shane

AU - Lambert, Galen

AU - Shin, Chae Young

AU - Santos, Nancy Dos

AU - Orlando, Krystal A.

AU - Lang, Jessica D.

AU - Hendricks, William P.D.

AU - Bally, Marcel B.

AU - Karnezis, Anthony

AU - Hass, Ralf

AU - Underhill, T. Michael

AU - Morin, Gregg B.

AU - Trent, Jeffrey M.

AU - Weissman, Bernard E.

AU - Huntsman, David G.

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