+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

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



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



Journal of Pathology 242(3): 371-383



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. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

(PDF emailed within 0-6 h: $19.90)

Accession: 060354267

Download citation: RISBibTeXText

PMID: 28444909

DOI: 10.1002/path.4912


Related references

In vitro and in vivo therapeutic approach for a small cell carcinoma of the ovary hypercalcaemic type using a SCCOHT-1 cellular model. Orphanet Journal of Rare Diseases 9: 126, 2015

Small cell carcinoma of the ovary: hypercalcaemic type. Journal of Obstetrics and Gynaecology 31(2): 199-200, 2011

Role of the EZH2 histone methyltransferase as a therapeutic target in cancer. Pharmacology and Therapeutics 165: 26-31, 2017

Histone Methyltransferase EZH2: A Therapeutic Target for Ovarian Cancer. Molecular Cancer Therapeutics 17(3): 591-602, 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 17(12): 2767-2779, 2018

No small surprise - small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour. Journal of Pathology 233(3): 209-214, 2014

Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker. Cancer Science 102(7): 1298-1305, 2011

Clinical, morphological and immunohistochemical evidence that small-cell carcinoma of the ovary of hypercalcaemic type (SCCOHT) may be a primitive germ-cell neoplasm. Histopathology 70(7): 1147-1154, 2017

SMARCA4 inactivating mutations cause concomitant Coffin-Siris syndrome, microphthalmia and small-cell carcinoma of the ovary hypercalcaemic type. Journal of Pathology 243(1): 9-15, 2017

Small cell carcinoma of the ovary of the hypercalcaemic type: an analysis of clinical and prognostic aspects of a rare disease on the basis of cases published in the literature. Archives of Gynecology and Obstetrics 284(5): 1277-1282, 2012

Loss of SMARCA4 (BRG1) protein expression as determined by immunohistochemistry in small-cell carcinoma of the ovary, hypercalcaemic type distinguishes these tumours from their mimics. Histopathology 69(5): 727-738, 2016

Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type. Journal of Pathology 238(3): 389-400, 2016

The histone methyltransferase WHSC1 is regulated by EZH2 and is important for ovarian clear cell carcinoma cell proliferation. Bmc Cancer 19(1): 455, 2019

Epigenetic therapy with 3-deazaneplanocin A, an inhibitor of the histone methyltransferase EZH2, inhibits growth of non-small cell lung cancer cells. Lung Cancer 78(2): 138-143, 2013

Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models. Molecular Cancer Therapeutics 16(5): 850-860, 2017