Abstract
Alterations of epigenetic proteins that modulate the gene repressive lysine 27 on histone H3 (H3K27me) are recurrent features in cancers, including multiple myeloma (MM). The histone demethylase UTX/KDM6A, mutated in up to 10% of cases of MM activates genes by removing the H3K27me3 repressive histone mark, counteracting EZH2. RNA-sequencing studies showed that UTX upregulated genes in association with loss of H3K27me. Treatment of MM cell lines with an EZH2 inhibitor preferentially slowed growth of UTX-null cells. EZH2 inhibitors activated many of the same genes as UTX but also induced the earlier stage B cell marker Bcl6 which, in turn, shut off the late B cell IRF4 and MYC, leading to cell death.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Cell Death
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Cell Line, Tumor
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Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors
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Enhancer of Zeste Homolog 2 Protein / genetics
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Enhancer of Zeste Homolog 2 Protein / metabolism
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Epigenesis, Genetic
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Female
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Gene Expression Regulation, Neoplastic
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Histone Demethylases / genetics
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Histone Demethylases / metabolism*
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Histones / metabolism*
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Humans
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Interferon Regulatory Factors / genetics
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Interferon Regulatory Factors / metabolism
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Methylation
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Mice, Inbred C57BL
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Mice, Nude
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Multiple Myeloma / drug therapy
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Multiple Myeloma / genetics
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Multiple Myeloma / metabolism*
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Multiple Myeloma / pathology
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Mutation
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-6 / genetics
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Proto-Oncogene Proteins c-bcl-6 / metabolism
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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BCL6 protein, human
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Histones
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Interferon Regulatory Factors
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MYC protein, human
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Nuclear Proteins
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Proto-Oncogene Proteins c-bcl-6
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Proto-Oncogene Proteins c-myc
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interferon regulatory factor-4
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Histone Demethylases
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KDM6A protein, human
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein