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

• DOI: 10.1210/me.2015-1310
• Publication Date: 2016-05-24T17:07:13Z
• Authors: Quan Wang; Lindsey S. Trevino; Rebecca Lee Yean ...; Mario Medvedovic; Jing Chen; Shuk-mei Ho; Jianjun Shen; Charles E. Foulds; Cristian Coarfa; Bert W. O'Malley; Ali Shilatifard; Cheryl L. Walker
• Keywords: Male; 0301 basic medicine; Chromatin Immunoprecipitation; Blotting, Western; Prostatic Neoplasms; Environmental Exposure; Histone-Lysine N-Methyltransferase; Methyltransferases; Endocrine Disruptors; Immunohistochemistry; Epigenesis, Genetic; Neoplasm Proteins; 3. Good health; DNA-Binding Proteins; Histones; Disease Models, Animal; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; HEK293 Cells; MCF-7 Cells; Animals; Humans; Myeloid-Lymphoid Leukemia Protein

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.