PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression | Zendy

Eneda Toska | Zendy; Pau Castel | Zendy; Sagar Chhangawala | Zendy; Amaia Arruabarrena-Aristorena | Zendy; Carmen Chan | Zendy; Vasilis Hristidis | Zendy; Emiliano Cocco | Zendy; Mirna Sallaku | Zendy; Guotai Xu | Zendy; Jane Park | Zendy; Gerard Minuesa | Zendy; Sophie Shifman | Zendy; Nicholas D. Socci | Zendy; Richard P. Koche | Zendy; Christina Leslie | Zendy; Maurizio Scaltriti | Zendy; José Baselga | Zendy

Open Access

PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression

Author(s) -

Eneda Toska,

Pau Castel,

Sagar Chhangawala,

Amaia Arruabarrena-Aristorena,

Carmen Chan,

Vasilis Hristidis,

Emiliano Cocco,

Mirna Sallaku,

Guotai Xu,

Jane Park,

Gerard Minuesa,

Sophie Shifman,

Nicholas D. Socci,

Richard P. Koche,

Christina Leslie,

Maurizio Scaltriti,

José Baselga

Publication year - 2019

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2019.02.111

Subject(s) - sgk1 , chromatin , pi3k/akt/mtor pathway , microbiology and biotechnology , biology , chromatin immunoprecipitation , phosphorylation , chromatin remodeling , protein kinase b , histone h3 , transcriptional regulation , cancer research , transcription factor , signal transduction , gene expression , promoter , genetics , gene

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.

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