Dominant-negative histone H3 lysine 27 mutant derepresses silenced tumor suppressor genes and reverses the drug-resistant phenotype in cancer cells

Phillip H. Abbosh, John S. Montgomery, Jason A. Starkey, Milos Novotny, Eleanor G. Zuhowski, Merrill J. Egorin, Annie P. Moseman, Adam Golas, Kate M. Brannon, Curtis Balch, Hui-ming Huang, Kenneth P. Nephew

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5582-5591
Number of pages10
JournalCancer Research
Volume66
Issue number11
DOIs
StatePublished - Jun 1 2006
Externally publishedYes

Fingerprint

Tumor Suppressor Genes
Histones
Methylation
Lysine
Histone Code
Phenotype
DNA Methylation
Epigenomics
Pharmaceutical Preparations
Neoplasms
Platinum
Ovarian Neoplasms
Neoplastic Processes
DNA Adducts
Gene Silencing
Cisplatin
Chromatin
Cell Line
DNA
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Abbosh, P. H., Montgomery, J. S., Starkey, J. A., Novotny, M., Zuhowski, E. G., Egorin, M. J., ... Nephew, K. P. (2006). Dominant-negative histone H3 lysine 27 mutant derepresses silenced tumor suppressor genes and reverses the drug-resistant phenotype in cancer cells. Cancer Research, 66(11), 5582-5591. https://doi.org/10.1158/0008-5472.CAN-05-3575

Dominant-negative histone H3 lysine 27 mutant derepresses silenced tumor suppressor genes and reverses the drug-resistant phenotype in cancer cells. / Abbosh, Phillip H.; Montgomery, John S.; Starkey, Jason A.; Novotny, Milos; Zuhowski, Eleanor G.; Egorin, Merrill J.; Moseman, Annie P.; Golas, Adam; Brannon, Kate M.; Balch, Curtis; Huang, Hui-ming; Nephew, Kenneth P.

In: Cancer Research, Vol. 66, No. 11, 01.06.2006, p. 5582-5591.

Research output: Contribution to journalArticle

Abbosh, PH, Montgomery, JS, Starkey, JA, Novotny, M, Zuhowski, EG, Egorin, MJ, Moseman, AP, Golas, A, Brannon, KM, Balch, C, Huang, H & Nephew, KP 2006, 'Dominant-negative histone H3 lysine 27 mutant derepresses silenced tumor suppressor genes and reverses the drug-resistant phenotype in cancer cells', Cancer Research, vol. 66, no. 11, pp. 5582-5591. https://doi.org/10.1158/0008-5472.CAN-05-3575
Abbosh, Phillip H. ; Montgomery, John S. ; Starkey, Jason A. ; Novotny, Milos ; Zuhowski, Eleanor G. ; Egorin, Merrill J. ; Moseman, Annie P. ; Golas, Adam ; Brannon, Kate M. ; Balch, Curtis ; Huang, Hui-ming ; Nephew, Kenneth P. / Dominant-negative histone H3 lysine 27 mutant derepresses silenced tumor suppressor genes and reverses the drug-resistant phenotype in cancer cells. In: Cancer Research. 2006 ; Vol. 66, No. 11. pp. 5582-5591.
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AU - Moseman, Annie P.

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