Critical role of the fibroblast growth factor signalling pathway in Ewing's sarcoma octamer-binding transcription factor 4-mediated cell proliferation and tumorigenesis.

Publisher: Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies Country of Publication: England NLM ID: 101229646 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1742-4658 (Electronic) Linking ISSN: 1742464X NLM ISO Abbreviation: FEBS J Subsets: MEDLINE

Original Publication: Oxford, UK : Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies, c2005-

Cell Proliferation* ; Signal Transduction*; Carcinogenesis/*metabolism ; Fibroblast Growth Factor 4/*metabolism ; Octamer Transcription Factor-3/*genetics ; Oncogene Proteins, Fusion/*metabolism ; Soft Tissue Neoplasms/*metabolism; Animals ; Benzimidazoles/pharmacology ; Binding Sites ; Carcinogenesis/genetics ; Cell Line, Tumor ; Fibroblast Growth Factor 4/genetics ; Humans ; Imidazoles/pharmacology ; Mice ; Octamer Transcription Factor-3/metabolism ; Oncogene Proteins, Fusion/chemistry ; Oncogene Proteins, Fusion/genetics ; Protein Binding ; Pyridazines/pharmacology ; Pyrimidines/pharmacology ; Quinolones/pharmacology ; Receptors, Fibroblast Growth Factor/antagonists & inhibitors ; Soft Tissue Neoplasms/genetics

Certain bone and soft tissue (BST) tumours harbour a chromosomal translocation [t(6;22)(p21;q12)], which fuses the Ewing's sarcoma (EWS) gene at 22q12 with the octamer-binding transcription factor 4 (Oct-4) gene at 6p21, resulting in the chimeric EWS-Oct-4 protein that possesses high transactivation ability. Although abnormal activation of signalling pathways can lead to human cancer development, the pathways underlying these processes in human BST tumours remain poorly explored. Here, we investigated the functional significance of fibroblast growth factor (FGF) signalling in human BST tumours. To identify the gene(s) involved in the FGF signalling pathway and potentially regulated by EWS-Oct-4 (also called EWS-POU5F1), we performed RNA-Seq analysis, electrophoretic mobility shift assays, chromatin immunoprecipitation assays, and xenograft assays. Treating GBS6 or ZHBTc4 cells-expressing EWS-Oct-4 with the small molecule FGF receptor (FGFR) inhibitors PD173074, NVPBGJ398, ponatinib, and dovitinib suppressed cellular proliferation. Gene expression analysis revealed that, among 22 Fgf and four Fgfr family members, Fgf-4 showed the highest upregulation (by 145-fold) in ZHBTc4 cells-expressing EWS-Oct-4. Computer-assisted analysis identified a putative EWS-Oct-4-binding site at +3017/+3024, suggesting that EWS-Oct-4 regulates Fgf-4 expression in human BST tumours. Fgf-4 enhancer constructs showed that EWS-Oct-4 transactivated the Fgf-4 gene reporter in vitro, and that overexpression of EWS-Oct-4 stimulated endogenous Fgf-4 gene expression in vivo. Finally, PD173074 significantly decreased tumour volume in mice. Taken together, these data suggest that FGF-4 signalling is involved in EWS-Oct-4-mediated tumorigenesis, and that its inhibition impairs tumour growth in vivo significantly.
(© 2019 Federation of European Biochemical Societies.)

Comment in: FEBS J. 2019 Nov;286(22):4418-4421. (PMID: 31400091)

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2016R1D1A1B03932300 International National Research Foundation (NRF) of Korea; 2018M3A9H1023139 International Bio & Medical Technology Development Program

Keywords: EWS-Oct-4; FGF signalling; chromosomal translocation; fusion protein; human bone and soft tissue tumour

0 (4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one)
0 (Benzimidazoles)
0 (FGF4 protein, human)
0 (Fibroblast Growth Factor 4)
0 (Imidazoles)
0 (Octamer Transcription Factor-3)
0 (Oncogene Proteins, Fusion)
0 (PD 173074)
0 (POU5F1 protein, human)
0 (Pyridazines)
0 (Pyrimidines)
0 (Quinolones)
0 (Receptors, Fibroblast Growth Factor)
4340891KFS (ponatinib)

Date Created: 20190604 Date Completed: 20200615 Latest Revision: 20200615

20240829

10.1111/febs.14946

31155838