Journal
MOLECULAR ENDOCRINOLOGY
Volume 30, Issue 8, Pages 856-871Publisher
OXFORD UNIV PRESS INC
DOI: 10.1210/me.2015-1310
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Funding
- National Institute of Environmental Health Sciences Grants [RC2ES018789, P30ES023512, ES023206, U01 ES026719]
- Cancer Prevention Research Institute of Texas (CPRIT) Grant [RP120855]
- Welch Foundation (Houston, TX) [BE-0023]
- CPRIT Core Facility Support Award [RP120348, RP120092]
- Baylor College of Medicine Advanced Technology Core Bioinformatics Core
- National Cancer Institute Shared Resources Award [P30CA125123]
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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.
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