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

Cell Rep. 2019 Apr 2;27(1):294-306.e5. doi: 10.1016/j.celrep.2019.02.111.

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.

Keywords: AKT; KMT2D; PI3K inhibitors; PI3K pathway; SGK1; breast cancer; chromatin regulation; estrogen receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Chromatin Assembly and Disassembly*
  • DNA-Binding Proteins / metabolism
  • Feedback, Physiological*
  • HEK293 Cells
  • Histones / metabolism
  • Humans
  • Immediate-Early Proteins / genetics*
  • Immediate-Early Proteins / metabolism
  • MCF-7 Cells
  • Methylation
  • Neoplasm Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Estrogen / metabolism*
  • Signal Transduction / drug effects
  • Transcriptional Activation

Substances

  • DNA-Binding Proteins
  • Histones
  • Immediate-Early Proteins
  • KMT2D protein, human
  • Neoplasm Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Estrogen
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • serum-glucocorticoid regulated kinase