Research Paper Volume 13, Issue 10 pp 13739—13763
Glycogen synthase kinase-3 beta (GSK3β)-mediated phosphorylation of ETS1 promotes progression of ovarian carcinoma
- 1 Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- 2 Department of Pathology, Chang Gung Memorial Hospital, Linkou Medical Center, and Chang Gung University, Taoyuan, Taiwan
- 3 Clinical Proteomics Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- 4 Graduate Institute of Clinical Medical Science, Chang-Gung University, Taoyuan, Taiwan
- 5 Department of Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- 6 Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- 7 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Medical Center, and Chang Gung University, Taoyuan, Taiwan
- 8 Department of Biotechnology, Ming Chuan University, Taoyuan, Taiwan
Received: November 30, 2020 Accepted: March 14, 2021 Published: May 23, 2021
https://doi.org/10.18632/aging.202966How to Cite
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.
Abbreviations
GSK3β: glycogen synthase kinase-3β; MMP-9: matrix metalloproteinase-9; PKCα: protein kinase Cα; CaMKII: calcium-dependent protein kinase II; EGF: epidermal growth factor; VEGF: vascular endothelial growth factor; ERK: extracellular signal-regulated kinases; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; AP-1: activator protein 1; IOSE-80PC: The immortalized human ovarian surface epithelial cell line; ETS1-3A: ETS1 T265A/S269A/S273A mutants; ETS1-2A: ETS1 S272A/S276A mutants; ChIP assay: chromatin immunoprecipitation assay; Hh: hedgehog; KDM1A/LSD1: lysine-specific histone demethylase 1A; EMT: epithelial-mesenchymal transition; CHX: cycloheximide.