Synapse - PI3K inhibition activates SGK1 via a feedback loop to promote chromatin-based regulation of ER-dependent gene expression

PI3K inhibition activates SGK1 via a feedback loop to promote chromatin-based regulation of ER-dependent gene expression Journal Article

Authors:	Toska, E.; Castel, P.; Chhangawala, S.; Arruabarrena-Aristorena, A.; Chan, C.; Hristidis, V. C.; Cocco, E.; Sallaku, M.; Xu, G.; Park, J.; Minuesa, G.; Shifman, S. G.; Socci, N. D.; Koche, R.; Leslie, C. S.; Scaltriti, M.; Baselga, J.
Article Title:	PI3K inhibition activates SGK1 via a feedback loop to promote chromatin-based regulation of ER-dependent gene expression
Abstract:	The PI3K pathway integrates extracellular stimuli to phosphorylate effectors such as AKT and serum-and-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 PI3Kα 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. Toska, Castel, et al. show that the PI3K pathway propagates its effects to control chromatin and estrogen receptor (ER) function through SGK1, a PI3K effector. PI3K inhibitors, via a negative-feedback loop, activate SGK1, which phosphorylates the histone lysine methyltransferase KMT2D to attenuate its activity and regulate ER response. © 2019 The Author(s)
Keywords:	signal transduction; controlled study; unclassified drug; human cell; promoter region; nonhuman; protein function; enzyme inhibition; breast cancer; protein protein interaction; enzyme activation; phosphatidylinositol 3 kinase; gene expression regulation; enzyme phosphorylation; transcription regulation; chromatin; feedback system; negative feedback; estrogen receptor; akt; dna binding; serum and glucocorticoid regulated kinase 1; lysine; receptor binding; phosphatidylinositol 3 kinase inhibitor; histone lysine methyltransferase; histone h4; protein kinase b inhibitor; chromatin regulation; pi3k pathway; sgk1; human; priority journal; article; pi3k inhibitors; phosphatidylinositol 3 kinase alpha; kmt2d; kmt2d protein; sgk1 gene
Journal Title:	Cell Reports
Volume:	27
Issue:	1
ISSN:	2211-1247
Publisher:	Cell Press
Date Published:	2019-04-02
Start Page:	294
End Page:	306.e5
Language:	English
DOI:	10.1016/j.celrep.2019.02.111
PUBMED:	30943409
PROVIDER:	scopus
PMCID:	PMC6503687
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85062842261&doi=10.1016%2fj.celrep.2019.02.111&partnerID=40&md5=7fddfe0dc979d987d9021be2ba1bb915
Notes:	Source: Scopus