Journal article
EWS-FLI1 and Activator Protein-1 (AP-1) Reciprocally Regulate Extracellular-Matrix Proteins in Ewing sarcoma Cells
International journal of molecular sciences, Vol.25(16), 8595
08/06/2024
DOI: 10.3390/ijms25168595
PMCID: PMC11354993
PMID: 39201282
Abstract
Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis of deoxyribonucleotides and the target of multiple chemotherapy drugs, including gemcitabine. We previously identified that inhibition of RNR in Ewing sarcoma tumors upregulates the expression levels of multiple members of the activator protein-1 (AP-1) transcription factor family, including c-Jun and c-Fos, and downregulates the expression of c-Myc. However, the broader functions and downstream targets of AP-1, which are highly context- and cell-dependent, are unknown in Ewing sarcoma tumors. Consequently, in this work, we used genetically defined models, transcriptome profiling, and gene-set -enrichment analysis to identify that AP-1 and EWS-FLI1, the driver oncogene in most Ewing sarcoma tumors, reciprocally regulate the expression of multiple extracellular-matrix proteins, including fibronectins, integrins, and collagens. AP-1 expression in Ewing sarcoma cells also drives, concurrent with these perturbations in gene and protein expression, changes in cell morphology and phenotype. We also identified that EWS-FLI1 dysregulates the expression of multiple AP-1 proteins, aligning with previous reports demonstrating genetic and physical interactions between EWS-FLI1 and AP-1. Overall, these results provide novel insights into the distinct, EWS-FLI1-dependent features of Ewing sarcoma tumors and identify a novel, reciprocal regulation of extracellular-matrix components by EWS-FLI1 and AP-1.
Details
- Title: Subtitle
- EWS-FLI1 and Activator Protein-1 (AP-1) Reciprocally Regulate Extracellular-Matrix Proteins in Ewing sarcoma Cells
- Creators
- Emma E. Croushore - University of IowaChristopher S. Stipp - University of IowaDavid J. Gordon - University of Iowa
- Resource Type
- Journal article
- Publication Details
- International journal of molecular sciences, Vol.25(16), 8595
- Publisher
- MDPI
- DOI
- 10.3390/ijms25168595
- PMID
- 39201282
- PMCID
- PMC11354993
- ISSN
- 1422-0067
- eISSN
- 1422-0067
- Grant note
- Charlie Landers Foundation: R37-CA217910, P30CA086862 NCI: NCI P30CA086862
DJG is supported by The Matt Morrell and Natalie Sanchez Pediatric Cancer Research Foundation, the Stead Fund for Leadership Development & Innovation in Pediatric Medicine, Sammy's Superheroes, Cal's Angels, Unravel Pediatric Cancer, Hyundai Hope on Wheels, the Charlie Landers Foundation, and NIH Grant R37-CA217910. This work was also supported by a grant (P30CA086862) from the NCI, administered through the Holden Comprehensive Cancer Center at The University of Iowa. The authors would like to acknowledge use of the University of Iowa Flow Cytometry Facility and the RNA sequencing facility (Genomics Division of the Iowa Institute of Human Genetics) which are supported, in part, by the University of Iowa Carver College of Medicine and the Holden Comprehensive Cancer Center (NCI P30CA086862).
- Language
- English
- Date published
- 08/06/2024
- Academic Unit
- Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Biology; Hematology/Oncology
- Record Identifier
- 9984696863502771
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