Journal
CELL REPORTS
Volume 27, Issue 1, Pages 294-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.02.111
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Funding
- Stand Up to Cancer (Cancer Drug Combination Convergence Team)
- V Foundation
- National Science Foundation
- MSK Society Scholar Prize
- Jane Coffin Childs Memorial Fund
- NIH [P30 CA008748, RO1CA190642-01A1]
- Breast Cancer Research Foundation
- Geoffrey Beene Cancer Research Center
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The PI3K pathway integrates extracellular stimuli to phosphorylate effectors such as AKT and serumand- glucocorticoid-regulated kinase (SGK1). We have previously reported that the PI3K pathway regulates estrogen receptor (ER)-dependent transcription in breast cancer through the phosphorylation of the lysine methyltransferase KMT2D by AKT. Here, we show that PI3Ka inhibition, via a negative-feedback loop, activates SGK1 to promote chromatin-based regulation of ER-dependent transcription. PI3K/AKT inhibitors activate ER, which promotes SGK1 transcription through direct binding to its promoter. Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity. Thus, SGK1 regulates the chromatin landscape and ER-dependent transcription via the direct phosphorylation of KMT2D. These findings reveal an ER-SGK1-KMT2D signaling circuit aimed to attenuate ER response through a role for SGK1 to program chromatin and ER transcriptional output.
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