Abstract
Recently, studies have been suggested that H3K27me3 is implicated with maintenance of cancer stem cells (CSCs), however, the roles of H3K27me3 in Breast cancer stem cells (BCSCs) remain poorly investigated. Here we explore the functionallities of H3K27me3 on BCSCs, we identify H3K27me3 as a negative modulator of BCSCs and suggest GSKJ4 is a promising drug targeting BCSCs. We show that the H3K27me3 level is decreased in mammosphere-derived BCSCs. In breast cancer cells, we demonstrate that GSKJ4 could markedly inhibit the proliferation. Strikingly, we show that GSKJ4 could effectively suppress BCSCs including expansion, self-renewal capacity, and the expression of stemness-related markers. Additionally, our xenograft model confirms that GSKJ4 is able to effectively inhibit the tumorigenicity of MDA-MB-231. Mechanistically, the inhibition effects of GSKJ4 on BCSCs are via inhibiting demethylases JMJD3 and UTX with methyltransferase EZH2 unchanged, which enhances H3K27me3 level. H3K27me3 activating leads to reduction of BCSCs expansion, self-renewal and global level of stemness factors. Collectively, our results provide strong supports that H3K27me3 exerts a suppressive influence on BCSCs and reveal that GSKJ4 is capable to be a prospective agent targeting BCSCs.
Keywords:
Breast cancer stem cells; Epigenetic modification; GSKJ4; H3K27me3.
Copyright © 2017 Elsevier Inc. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Benzazepines / pharmacology*
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Cell Line, Tumor
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Enzyme Inhibitors / pharmacology*
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Female
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Gene Expression Regulation, Neoplastic*
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Histone Demethylases / antagonists & inhibitors
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Histone Demethylases / genetics
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Histone Demethylases / metabolism
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Humans
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Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
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Jumonji Domain-Containing Histone Demethylases / genetics
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Jumonji Domain-Containing Histone Demethylases / metabolism
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MCF-7 Cells
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Mice
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Mice, Nude
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Nanog Homeobox Protein / genetics
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Nanog Homeobox Protein / metabolism
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Octamer Transcription Factor-3 / genetics
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Octamer Transcription Factor-3 / metabolism
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Pyrimidines / pharmacology*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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SOXB1 Transcription Factors / genetics
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SOXB1 Transcription Factors / metabolism
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Signal Transduction
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Spheroids, Cellular / drug effects*
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Spheroids, Cellular / metabolism
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Spheroids, Cellular / pathology
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Benzazepines
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Enzyme Inhibitors
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GSK-J4
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NANOG protein, human
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Nanog Homeobox Protein
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Nuclear Proteins
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Octamer Transcription Factor-3
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POU5F1 protein, human
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Pyrimidines
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RNA, Small Interfering
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SOX2 protein, human
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SOXB1 Transcription Factors
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Histone Demethylases
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Jumonji Domain-Containing Histone Demethylases
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KDM6A protein, human
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KDM6B protein, human