Glycogen synthase kinase-3 beta (GSK3β)-mediated phosphorylation of ETS1 promotes progression of ovarian carcinoma

Aging (Albany NY). 2021 May 23;13(10):13739-13763. doi: 10.18632/aging.202966. Epub 2021 May 23.


ETS1 - an evolutionarily conserved transcription factor involved in the regulation of a number of cellular processes - is overexpressed in several malignancies, including ovarian cancer. Most studies on ETS1 expression have been focused on the transcriptional and RNA levels, with post-translational control mechanisms remaining relatively unexplored in the pathogenesis of malignancies. Here, we show that ETS1 forms a complex with glycogen synthase kinase-3β (GSK3β). Specifically, GSK3β-mediated phosphorylation of ETS1 at threonine 265 and serine 269 promoted protein stability, induced the transcriptional activation of matrix metalloproteinase (MMP)-9, and increased cell migration. In vivo experiments revealed that a GSK3β inhibitor was able to suppress both endogenous ETS1 expression and induction of MMP-9 expression. Upon generation of a specific antibody against phosphorylated ETS1, we demonstrated that phospho-ETS1 immunohistochemical expression in ovarian cancer specimens was correlated with that of MMP-9. Notably, the cumulative overall survival of patients with low phospho-ETS1 histoscores was significantly longer than that of those showing higher scores. We conclude that the GSK3β/ETS1/MMP-9 axis may regulate the biological aggressiveness of ovarian cancer and can serve as a prognostic factor in patients with this malignancy.

Keywords: ETS1; GSK3β; MMP-9; immunohistochemistry; ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Disease Progression*
  • Female
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Humans
  • Matrix Metalloproteinase 9 / metabolism
  • Mice, Inbred C57BL
  • Models, Biological
  • Mutation / genetics
  • Neoplasm Staging
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology*
  • Phosphorylation
  • Protein Binding
  • Protein Stability
  • Proto-Oncogene Protein c-ets-1 / chemistry
  • Proto-Oncogene Protein c-ets-1 / genetics
  • Proto-Oncogene Protein c-ets-1 / metabolism*
  • Serine / metabolism
  • Substrate Specificity
  • Threonine / metabolism


  • ETS1 protein, human
  • Proto-Oncogene Protein c-ets-1
  • Threonine
  • Serine
  • Glycogen Synthase Kinase 3 beta
  • Matrix Metalloproteinase 9