This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Abbosh, P. H. Articles by Nephew, K. P. Search for Related Content PubMed PubMed Citation Articles by Abbosh, P. H. Articles by Nephew, K. P.

Dominant-Negative Histone H3 Lysine 27 Mutant Derepresses Silenced Tumor Suppressor Genes and Reverses the Drug-Resistant Phenotype in Cancer Cells

¹ Medical Sciences, School of Medicine; ² Department of Chemistry, Indiana University, Bloomington, Indiana; ³ Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and ⁴ Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio

Requests for reprints: Kenneth P. Nephew, Medical Sciences, School of Medicine, Indiana University, 302 Jordan Hall, 1001 East 3rd Street, Bloomington, IN 47405-4401. Phone: 812-855-9445; Fax: 812-855-4436; E-mail: knephew{at}indiana.edu.

Histone modifications and DNA methylation are epigenetic phenomena that play a critical role in many neoplastic processes, including silencing of tumor suppressor genes. One such histone modification, particularly at H3 and H4, is methylation at specific lysine (K) residues. Whereas histone methylation of H3-K9 has been linked to DNA methylation and aberrant gene silencing in cancer cells, no such studies of H3-K27 have been reported. Here, we generated a stable cell line overexpressing a dominant-negative point mutant, H3-K27R, to examine the role of that specific lysine in ovarian cancer. Expression of this construct resulted in loss of methylation at H3-K27, global reduction of DNA methylation, and increased expression of tumor suppressor genes. One of the affected genes, RASSF1, was shown to be a direct target of H3-K27 methylation–mediated silencing. By increasing DNA-platinum adduct formation, indicating increased access of the drug to target DNA sequences, removal of H3-K27 methylation resensitized drug-resistant ovarian cancer cells to the chemotherapeutic agent cisplatin. This increased platinum-DNA access was likely due to relaxation of condensed chromatin. Our results show that overexpression of mutant H3-K27 in mammalian cells represents a novel tool for studying epigenetic mechanisms and the Histone Code Hypothesis in human cancer. Such findings show the significance of H3-K27 methylation as a promising target for epigenetic-based cancer therapies. (Cancer Res 2006; 66(11): 5582-91)

This article has been cited by other articles:

				C. Balch, F. Fang, D. E. Matei, T. H.-M. Huang, and K. P. Nephew Minireview: Epigenetic Changes in Ovarian Cancer Endocrinology, September 1, 2009; 150(9): 4003 - 4011. [Abstract] [Full Text] [PDF]

				A. V. Ougolkov, V. N. Bilim, and D. D. Billadeau Regulation of Pancreatic Tumor Cell Proliferation and Chemoresistance by the Histone Methyltransferase Enhancer of Zeste Homologue 2 Clin. Cancer Res., November 1, 2008; 14(21): 6790 - 6796. [Abstract] [Full Text] [PDF]

				Y. Watanabe, M. Toyota, Y. Kondo, H. Suzuki, T. Imai, M. Ohe-Toyota, R. Maruyama, M. Nojima, Y. Sasaki, Y. Sekido, et al. PRDM5 Identified as a Target of Epigenetic Silencing in Colorectal and Gastric Cancer Clin. Cancer Res., August 15, 2007; 13(16): 4786 - 4794. [Abstract] [Full Text] [PDF]

				K. M. McGarvey, E. Greene, J. A. Fahrner, T. Jenuwein, and S. B. Baylin DNA Methylation and Complete Transcriptional Silencing of Cancer Genes Persist after Depletion of EZH2 Cancer Res., June 1, 2007; 67(11): 5097 - 5102. [Abstract] [Full Text] [PDF]