Reprogramming of the Epigenome by MLL1 Links Early-Life Environmental Exposures to Prostate Cancer Risk

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2016-08, Vol.30 (8), p.856-871
• Main 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
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Chromatin Immunoprecipitation; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; 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; Male; MCF-7 Cells; Methyltransferases - genetics; Methyltransferases - metabolism; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Original Research; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Prostatic Neoplasms - etiology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - genetics; RNA, Small Interfering - physiology; Signal Transduction - drug effects; Signal Transduction - genetics
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2015-1310

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.