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

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

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 methylat...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Vol. 66; no. 11; pp. 5582 - 5591
Main Authors: ABBOSH, Phillip H, MONTGOMERY, John S, HUANG, Tim H. M, NEPHEW, Kenneth P, STARKEY, Jason A, NOVOTNY, Milos, ZUHOWSKI, Eleanor G, EGORIN, Merrill J, MOSEMAN, Annie P, GOLAS, Adam, BRANNON, Kate M, BALCH, Curtis
Format: Journal Article
Language:English
Published: Philadelphia, PA American Association for Cancer Research 01-06-2006
Subjects:
Antineoplastic agents
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
Chromatin - metabolism
Cisplatin - pharmacology
CpG Islands
DNA Methylation
Doxorubicin - pharmacology
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Neoplastic - physiology
Gene Silencing
Genes, Tumor Suppressor
Histones - genetics
Humans
Lysine - genetics
Medical sciences
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - genetics
Pharmacology. Drug treatments
Point Mutation
Tumor Suppressor Proteins - genetics
Tumors
Gene silencing
Phenotype
Treatment resistance
Lysine
Aminoacid
Recessive character
Mutation
Malignant tumor
Tumor cell
Histone H3
Tumor suppressor gene
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Summary: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.
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ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-05-3575