Abstract
Histone methylation is implicated in various biological and pathological processes including cancer development. In this study, we discovered that ectopic expression of KDM5B, a histone H3 lysine 4 (H3K4) demethylase, promoted epithelial-mesenchymal transition (EMT) of cancer cells. KDM5B increased the expression of transcription factors, ZEB1 and ZEB2, followed by downregulation of E-cadherin and upregulation of mesenchymal marker genes. The expression of the microRNA-200 (miR-200) family, which specifically targets ZEB1 and ZEB2, was reduced in the cells with KDM5B overexpression. We found that KDM5B repressed the expression of the miR-200 family by changing histone H3 methylation status of their regulatory regions. The introduction of miR-200 precursor in the cells inhibited EMT induction by KDM5B, suggesting that miR-200 family was a critical downstream mediator of KDM5B-promoted EMT. Furthermore, knockdown of KDM5B was shown to affect the expression of EMT-related genes, indicating the involvement of endogenous KDM5B. Our study demonstrated a novel role of KDM5B histone lysine demethylase in EMT, which may contribute to malignant progression of cancer.
Keywords:
epithelial-mesenchymal transition; histone methylation; microRNA; transcription; tumor progression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD
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Cadherins / genetics
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Cadherins / metabolism
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Carcinogenesis / genetics
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Carcinogenesis / metabolism
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Cell Line, Tumor
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Cell Shape
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Epigenesis, Genetic
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Epithelial-Mesenchymal Transition*
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Fibronectins / genetics
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Fibronectins / metabolism
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Gene Expression Regulation, Neoplastic*
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Histones / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Jumonji Domain-Containing Histone Demethylases / physiology*
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Methylation
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Mice
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Nuclear Proteins / physiology*
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Protein Processing, Post-Translational
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Repressor Proteins / physiology*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic
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Zinc Finger E-box Binding Homeobox 2
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Zinc Finger E-box-Binding Homeobox 1
Substances
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Antigens, CD
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CDH1 protein, human
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Cadherins
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FN1 protein, human
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Fibronectins
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Histones
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Homeodomain Proteins
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MIRN200 microRNA, human
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MicroRNAs
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Nuclear Proteins
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Repressor Proteins
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Transcription Factors
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ZEB1 protein, human
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ZEB2 protein, human
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Zinc Finger E-box Binding Homeobox 2
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Zinc Finger E-box-Binding Homeobox 1
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Jumonji Domain-Containing Histone Demethylases
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KDM5B protein, human