Abstract
Tissue and organ development is a time of exquisite sensitivity to environmental exposures, which can reprogram developing tissues to increase susceptibility to adult diseases, including cancer. In the developing prostate, even brief exposure to endocrine-disrupting chemicals (EDCs) can increase risk for developing cancer in adulthood, with disruption of the epigenome thought to play a key role in this developmental reprogramming. We find that EDC-induced nongenomic phosphoinositide 3-kinase; (PI3K) signaling engages the histone methyltransferase mixed-lineage leukemia 1 (MLL1), responsible for the histone H3 lysine 4 trimethylation (H3K4me3) active epigenetic mark, to increase cleavage and formation of active MLL1 dimers. In the developing prostate, EDC-induced MLL1 activation increased H3K4me3 at genes associated with prostate cancer, with increased H3K4me3 and elevated basal and hormone-induced expression of reprogrammed genes persisting into adulthood. These data identify a mechanism for MLL1 activation that is vulnerable to disruption by environmental exposures, and link MLL1 activation by EDCs to developmental reprogramming of genes involved in prostate cancer.
MeSH terms
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Animals
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Blotting, Western
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Chromatin Immunoprecipitation
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Disease Models, Animal
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Endocrine Disruptors / toxicity
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Environmental Exposure / adverse effects
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Epigenesis, Genetic / drug effects
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Epigenesis, Genetic / genetics*
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HEK293 Cells
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Histone-Lysine N-Methyltransferase / genetics*
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Histone-Lysine N-Methyltransferase / metabolism*
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Histones / metabolism
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Humans
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Immunohistochemistry
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MCF-7 Cells
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Male
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Methyltransferases / genetics
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Methyltransferases / metabolism*
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Myeloid-Lymphoid Leukemia Protein / genetics*
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Myeloid-Lymphoid Leukemia Protein / metabolism*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Prostatic Neoplasms / etiology
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / physiology
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Rats
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Rats, Sprague-Dawley
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Signal Transduction / genetics
Substances
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DNA-Binding Proteins
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Endocrine Disruptors
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Histones
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KMT2A protein, human
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KMT2D protein, human
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Neoplasm Proteins
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RNA, Small Interfering
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Myeloid-Lymphoid Leukemia Protein
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DOT1L protein, human
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Methyltransferases
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Histone-Lysine N-Methyltransferase
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Phosphatidylinositol 3-Kinases