Abstract
Chemoresistance is a major unmet clinical obstacle in ovarian cancer treatment. Epigenetics plays a pivotal role in regulating the malignant phenotype, and has the potential in developing therapeutically valuable targets that improve the dismal outcome of this disease. Here we show that a series of transcription factors, including C/EBPβ, GCM1, and GATA1, could act as potential modulators of histone methylation in tumor cells. Of note, C/EBPβ, an independent prognostic factor for patients with ovarian cancer, mediates an important mechanism through which epigenetic enzyme modifies groups of functionally related genes in a context-dependent manner. By recruiting the methyltransferase DOT1L, C/EBPβ can maintain an open chromatin state by H3K79 methylation of multiple drug-resistance genes, thereby augmenting the chemoresistance of tumor cells. Therefore, we propose a new path against cancer epigenetics in which identifying and targeting the key regulators of epigenetics such as C/EBPβ may provide more precise therapeutic options in ovarian cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Biomarkers, Tumor / genetics*
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Biomarkers, Tumor / metabolism
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CCAAT-Enhancer-Binding Protein-beta / genetics*
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CCAAT-Enhancer-Binding Protein-beta / metabolism
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Cell Line, Tumor
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Chromatin / chemistry
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Chromatin / metabolism*
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Cisplatin / pharmacology
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DNA-Binding Proteins
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Databases, Factual
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Drug Resistance, Neoplasm / genetics*
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Epigenesis, Genetic*
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Female
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GATA1 Transcription Factor / genetics
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GATA1 Transcription Factor / metabolism
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GATA4 Transcription Factor / genetics
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GATA4 Transcription Factor / metabolism
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Histone-Lysine N-Methyltransferase
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Histones / genetics*
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Histones / metabolism
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Humans
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Interferon Regulatory Factor-3 / genetics
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Interferon Regulatory Factor-3 / metabolism
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Methylation
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Methyltransferases / genetics
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Methyltransferases / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / genetics*
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Ovarian Neoplasms / mortality
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Ovarian Neoplasms / pathology
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Primary Cell Culture
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Prognosis
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Survival Analysis
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Antineoplastic Agents
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Biomarkers, Tumor
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CCAAT-Enhancer-Binding Protein-beta
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Chromatin
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DNA-Binding Proteins
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GATA1 Transcription Factor
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GATA1 protein, human
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GATA4 Transcription Factor
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GATA4 protein, human
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GCM1 protein, human
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Histones
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Nuclear Proteins
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Transcription Factors
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DOT1L protein, human
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Methyltransferases
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Histone-Lysine N-Methyltransferase
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Cisplatin