Reprogramming of the Epigenome by MLL1 Links Early-Life Environmental Exposures to Prostate Cancer Risk.
Quan WangLindsey S TrevinoRebecca Lee Yean WongMario MedvedovicJing ChenShuk-Mei HoJianjun ShenCharles E FouldsCristian CoarfaBert W O'MalleyAli ShilatifardCheryl L WalkerPublished in: Molecular endocrinology (Baltimore, Md.) (2016)
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.
Keyphrases
- prostate cancer
- acute myeloid leukemia
- early life
- dna methylation
- radical prostatectomy
- high glucose
- diabetic rats
- air pollution
- protein protein
- gene expression
- papillary thyroid
- drug induced
- squamous cell
- depressive symptoms
- genome wide
- human health
- bone marrow
- binding protein
- big data
- oxidative stress
- lymph node metastasis
- squamous cell carcinoma
- protein kinase
- artificial intelligence
- single cell
- amino acid