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Research Paper|Volume 13, Issue 10|pp 13739—13763

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

Chia-Lung Tsai1, Shih-Ming Jung2, Lang-Ming Chi3, Chi-Neu Tsai4,5, Chiao-Yun Lin6, Angel Chao6,7, Yun-Shien Lee1,8
  • 1Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan
  • 2Department of Pathology, Chang Gung Memorial Hospital, Linkou Medical Center, and Chang Gung University, Taoyuan, Taiwan
  • 3Clinical Proteomics Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan
  • 4Graduate Institute of Clinical Medical Science, Chang-Gung University, Taoyuan, Taiwan
  • 5Department of Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
  • 6Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
  • 7Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Medical Center, and Chang Gung University, Taoyuan, Taiwan
  • 8Department of Biotechnology, Ming Chuan University, Taoyuan, Taiwan
* Equal contribution
Received: November 30, 2020Accepted: March 14, 2021Published: May 23, 2021
https://doi.org/10.18632/aging.202966

Copyright: © 2021 Tsai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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.