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

Area of Science:

• Molecular Biology
• Cellular Signaling
• Epigenetics

Background:

• The phosphoinositide 3-kinase (PI3K) pathway is crucial for integrating extracellular signals and regulating cellular processes via effectors like AKT and serum-and-glucocorticoid-regulated kinase (SGK1).
• Previously, our research demonstrated that the PI3K pathway influences estrogen receptor (ER)-dependent transcription in breast cancer, mediated by AKT-dependent phosphorylation of lysine methyltransferase KMT2D.

Purpose of the Study:

• To investigate the role of PI3Kα inhibition and its impact on SGK1 activation.
• To elucidate the mechanism by which SGK1 influences ER-dependent transcription and chromatin regulation.
• To identify a novel signaling circuit involving ER, SGK1, and KMT2D in breast cancer.

Main Methods:

• Utilized PI3K/AKT inhibitors to study pathway activation.
• Investigated the transcriptional regulation of SGK1 by ER.
• Examined the phosphorylation of KMT2D by SGK1 and its effect on histone H3 lysine 4 (H3K4) methylation.
• Analyzed chromatin states at ER loci.

Main Results:

• PI3Kα inhibition triggers a negative-feedback loop, activating SGK1.
• Activated ER directly promotes SGK1 transcription.
• Elevated SGK1 phosphorylates KMT2D, inhibiting its function and reducing H3K4 methylation at ER loci.
• This leads to a repressive chromatin state, attenuating ER activity.

Conclusions:

• SGK1 plays a key role in regulating the chromatin landscape and ER-dependent transcription through direct phosphorylation of KMT2D.
• A novel ER-SGK1-KMT2D signaling axis has been identified, which serves to attenuate ER response.
• SGK1's function in programming chromatin and ER transcriptional output is critical in this pathway.