Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2019-04, Vol.27 (1), p.294-306.e5

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Estrogen receptor (ER) activates SGK1 upon PI3Kα pathway inhibition•SGK1 directly phosphorylates KMT2D, resulting in the attenuation of its function•SGK1 induces a repressive chromatin state and a loss of H3K4me1/2 binding at ER loci•SGK1 regulates ER-dependent gene expression 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.