Abstract
Human colorectal cancer stem cells (CSCs) are tumour initiating cells that can self-renew and are highly tumorigenic and chemoresistant. While genetic mutations associated with human colorectal cancer development are well-known, little is known about how and whether epigenetic factors specifically contribute to the functional properties of human colorectal CSCs. Here we report that the KDM3 family of histone demethylases plays an important role in tumorigenic potential and survival of human colorectal CSCs by epigenetically activating Wnt target gene transcription. The depletion of KDM3 inhibits tumorigenic growth and chemoresistance of human colorectal CSCs. Mechanistically, KDM3 not only directly erases repressive H3K9me2 marks, but also helps to recruit histone methyltransferase MLL1 to promote H3K4 methylation, thereby promoting Wnt target gene transcription. Our results suggest that KDM3 is a critical epigenetic factor in Wnt signalling that orchestrates chromatin changes and transcription in human colorectal CSCs, identifying potential therapeutic targets for effective elimination of CSCs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carcinogenesis / genetics
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Cell Line, Tumor
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Cell Proliferation / genetics
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Chromatin / genetics
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Chromatin / metabolism
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Colorectal Neoplasms / genetics*
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Colorectal Neoplasms / pathology
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Colorectal Neoplasms / surgery
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DNA Methylation / genetics
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Epigenesis, Genetic
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Female
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Gene Expression Regulation, Neoplastic
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Histone-Lysine N-Methyltransferase / metabolism
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Histones / genetics
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Histones / metabolism
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Humans
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Jumonji Domain-Containing Histone Demethylases / genetics
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Jumonji Domain-Containing Histone Demethylases / metabolism*
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Mice, Inbred NOD
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Mice, Nude
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Mice, SCID
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Myeloid-Lymphoid Leukemia Protein / metabolism
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Oxidoreductases, N-Demethylating / genetics
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Oxidoreductases, N-Demethylating / metabolism*
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Wnt Signaling Pathway / genetics*
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Xenograft Model Antitumor Assays
Substances
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Chromatin
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Histones
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KMT2A protein, human
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Myeloid-Lymphoid Leukemia Protein
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JMJD1C protein, human
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Jumonji Domain-Containing Histone Demethylases
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KDM3A protein, human
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KDM3B protein, human
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Oxidoreductases, N-Demethylating
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Histone-Lysine N-Methyltransferase