Title: Reprogramming of the Epigenome by MLL1 Links Early-Life Environmental Exposures to Prostate Cancer Risk.
Authors: Wang, Quan; Trevino, Lindsey S; Wong, Rebecca Lee Yean; Medvedovic, Mario; Chen, Jing; Ho, Shuk-Mei; Shen, Jianjun; Foulds, Charles E; Coarfa, Cristian; O'Malley, Bert W; Shilatifard, Ali; Walker, Cheryl L
Published In Mol Endocrinol, (2016 Aug)
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.
PubMed ID: 27219490
MeSH Terms: Animals; Blotting, Western; Chromatin Immunoprecipitation; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism*; Disease Models, Animal; Endocrine Disruptors/toxicity; Environmental Exposure/adverse effects; Epigenesis, Genetic/drug effects; Epigenesis, Genetic/genetics*; HEK293 Cells; Histone-Lysine N-Methyltransferase/genetics*; Histone-Lysine N-Methyltransferase/metabolism*; Histones/metabolism; Humans; Immunohistochemistry; MCF-7 Cells; Male; Methyltransferases/genetics; Methyltransferases/metabolism*; Myeloid-Lymphoid Leukemia Protein/genetics*; Myeloid-Lymphoid Leukemia Protein/metabolism*; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism*; Phosphatidylinositol 3-Kinases/genetics; Phosphatidylinositol 3-Kinases/metabolism; Prostatic Neoplasms/etiology; Prostatic Neoplasms/genetics; Prostatic Neoplasms/metabolism*; RNA, Small Interfering/genetics; RNA, Small Interfering/physiology; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction/drug effects; Signal Transduction/genetics