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Histone modifications silence the GATA transcription factor genes in ovarian cancer

Oncogene volume 25, pages 5446–5461 (2006)Cite this article

Abstract

Altered expression of GATA factors was found and proposed as the underlying mechanism for dedifferentiation in ovarian carcinogenesis. In particular, GATA6 is lost or excluded from the nucleus in 85% of ovarian tumors and GATA4 expression is absent in majority of ovarian cancer cell lines. Here, we evaluated their DNA and histone epigenetic modifications in five ovarian epithelial and carcinoma cell lines (human ‘immortalized’ ovarian surface epithelium (HIO)-117, HIO-114, A2780, SKOV3 and ES2). GATA4 and GATA6 gene silencing was found to correlate with hypoacetylation of histones H3 and H4 and loss of histone H3/lysine K4 tri-methylation at their promoters in all lines. Conversely, histone H3/lysine K9 di-methylation and HP1γ association were not observed, excluding reorganization of GATA genes into heterochromatic structures. The histone deacetylase inhibitor trichostatin A, but not the DNA methylation inhibitor 5′-aza-2′-deoxycytidine, re-established the expression of GATA4 and/or GATA6 in A2780 and HIO-114 cells, correlating with increased histone H3 and H4 acetylation, histone H3 lysine K4 methylation and DNase I sensitivity at the promoters. Therefore, altered histone modification of the promoter loci is one mechanism responsible for the silencing of GATA transcription factors and the subsequent loss of a target gene, the tumor suppressor Disabled-2, in ovarian carcinogenesis.

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Acknowledgements

We appreciate Dr Elizabeth Smith for reading and commenting during the process of preparing the paper. We acknowledge the assistance by the Histopathology Facility, the DNA Sequencing Facility, the Fannie E Rippel Biochemistry and Biotechnology Facility, and the Cell Culture Facility of Fox Chase Cancer Center. Drs Kathy Qi Cai, Paul Cairns and Andrew Godwin are greatly appreciated for their intellectual and technical advice in performing these experiments. We thank Malgorzata Rula, Lisa Vanderveer and Jennifer Smedberg for their technical assistance, and Ms Patricia Bateman for her excellent secretarial support. This work was supported by grants R01 CA79716 and R01 CA75389 to XX Xu from NCI, NIH, funds from Ovarian Cancer SPORE P50 CA83638 (RF Ozols, PI), and the Core Grant #CA006927. The work was also supported by an appropriation from the Commonwealth of Pennsylvania.

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  1. C Caslini

    Present address: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

Authors and Affiliations

  1. Department of Medical Oncology, Ovarian Cancer and Tumor Cell Biology Programs, Fox Chase Cancer Center, Philadelphia, PA, USA

    C Caslini, C D Capo-chichi, I H Roland & X-X Xu

  2. Basic Science and Fannie E Rippel Biochemistry and Biotechnology Facility, Fox Chase Cancer Center, Philadelphia, PA, USA

    E Nicolas & A T Yeung

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  1. C Caslini
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Correspondence to X-X Xu.

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Caslini, C., Capo-chichi, C., Roland, I. et al. Histone modifications silence the GATA transcription factor genes in ovarian cancer. Oncogene 25, 5446–5461 (2006). https://doi.org/10.1038/sj.onc.1209533

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