Targeting CD99 Compromises the Oncogenic Effects of the Chimera EWS-FLI1 by Inducing Reexpression of Zyxin and Inhibition of GLI1 Activity.
Animals
Humans
Mice
12E7 Antigen
/ metabolism
Mice, Nude
Oncogene Proteins, Fusion
/ metabolism
Oncogenes
/ genetics
Proto-Oncogene Protein c-fli-1
/ metabolism
RNA-Binding Protein EWS
/ metabolism
Sarcoma, Ewing
/ genetics
Transfection
Zinc Finger Protein GLI1
/ antagonists & inhibitors
Zyxin
/ genetics
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
02
03
2021
revised:
30
07
2021
accepted:
12
10
2021
pubmed:
21
10
2021
medline:
31
3
2022
entrez:
20
10
2021
Statut:
ppublish
Résumé
Ewing sarcoma, a highly aggressive pediatric tumor, is driven by EWS-FLI1, an oncogenic transcription factor that remodels the tumor genetic landscape. Epigenetic mechanisms play a pivotal role in Ewing sarcoma pathogenesis, and the therapeutic value of compounds targeting epigenetic pathways is being identified in preclinical models. Here, we showed that modulation of CD99, a cell surface molecule highly expressed in Ewing sarcoma cells, may alter transcriptional dysregulation in Ewing sarcoma through control of the zyxin-GLI1 axis. Zyxin is transcriptionally repressed, but GLI1 expression is maintained by EWS-FLI1. We demonstrated that targeting CD99 with antibodies, including the human diabody C7, or genetically inhibiting CD99 is sufficient to increase zyxin expression and induce its dynamic nuclear accumulation. Nuclear zyxin functionally affects GLI1, inhibiting targets such as NKX2-2, cyclin D1, and PTCH1 and upregulating GAS1, a tumor suppressor protein negatively regulated by SHH/GLI1 signaling. We used a battery of functional assays to demonstrate (i) the relationship between CD99/zyxin and tumor cell growth/migration and (ii) how CD99 deprivation from the Ewing sarcoma cell surface is sufficient to specifically affect the expression of some crucial EWS-FLI1 targets, both
Identifiants
pubmed: 34667115
pii: 1535-7163.MCT-21-0189
doi: 10.1158/1535-7163.MCT-21-0189
doi:
Substances chimiques
12E7 Antigen
0
Cd99 protein, mouse
0
EWS-FLI fusion protein
0
Oncogene Proteins, Fusion
0
Proto-Oncogene Protein c-fli-1
0
RNA-Binding Protein EWS
0
Zinc Finger Protein GLI1
0
Zyxin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
58-69Informations de copyright
©2021 American Association for Cancer Research.
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