Format

Send to

Choose Destination
Mol Cancer Ther. 2018 Dec;17(12):2767-2779. doi: 10.1158/1535-7163.MCT-18-0348. Epub 2018 Sep 19.

Histone Deacetylase Inhibitors Synergize with Catalytic Inhibitors of EZH2 to Exhibit Antitumor Activity in Small Cell Carcinoma of the Ovary, Hypercalcemic Type.

Author information

1
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. yewang@bccrc.ca dhuntsma@bccancer.bc.ca.
2
Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
3
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
4
Michael Smith Genome Science Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
5
Department of Experimental Therapeutics, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
6
Department of Pathology and Laboratory Medicine and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
7
Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, Arizona.
8
Department of Obstetrics and Gynecology, Hannover Medical School, D-30625 Hannover, Germany.
9
Department of Cellular and Physiological Sciences and Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada.
10
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
11
Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC, Canada.

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.

PMID:
30232145
PMCID:
PMC6279577
[Available on 2019-12-01]
DOI:
10.1158/1535-7163.MCT-18-0348
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center