TY - JOUR
T1 - Reprogramming of the epigenome by MLL1 links early-life environmental exposures to prostate cancer risk
AU - Wang, Quan
AU - Trevino, Lindsey S.
AU - Wong, Rebecca Lee Yean
AU - Medvedovic, Mario
AU - Chen, Jing
AU - Ho, Shuk Mei
AU - Shen, Jianjun
AU - Foulds, Charles E.
AU - Coarfa, Cristian
AU - O’Malley, Bert W.
AU - Shilatifard, Ali
AU - Walker, Cheryl L.
N1 - Publisher Copyright:
© 2016 by the Endocrine Society.
PY - 2016/8
Y1 - 2016/8
N2 - 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.
AB - 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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U2 - 10.1210/me.2015-1310
DO - 10.1210/me.2015-1310
M3 - Article
C2 - 27219490
AN - SCOPUS:84980348133
SN - 0888-8809
VL - 30
SP - 856
EP - 871
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 8
ER -