EWS/FLI is a Master Regulator of Metabolic Reprogramming in Ewing Sarcoma

Ewing sarcoma is a bone malignancy driven by a translocation event resulting in the fusion protein EWS/FLI1 (EF). EF functions as an aberrant and oncogenic transcription factor that misregulates the expression of thousands of genes. Previous work has focused principally on determining important tran...

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Bibliographic Details
Published in:Molecular cancer research 2017-11, Vol.15 (11), p.1517-1530
Main Authors: Tanner, Jason M, Bensard, Claire, Wei, Peng, Krah, Nathan M, Schell, John C, Gardiner, Jamie, Schiffman, Joshua, Lessnick, Stephen L, Rutter, Jared
Format: Article
Language:English
Subjects:
Aberration
Biological effects
Biology
Biosynthesis
Bone Neoplasms - genetics
Bone Neoplasms - metabolism
Cell death
Cell Line, Tumor
Ewing's sarcoma
Fusion protein
Gene expression
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Glycolysis
Humans
Malignancy
Metabolic Networks and Pathways
Metabolic pathways
Metabolism
Metabolites
Metabolomics
Metabolomics - methods
Methylation
Mitochondria
Oncogene Proteins, Fusion - genetics
Oncogene Proteins, Fusion - metabolism
Partnerships
Pharmacology
Phosphoglycerate dehydrogenase
Phosphoglycerate Dehydrogenase - metabolism
Protein transport
Proto-Oncogene Protein c-fli-1 - genetics
Proto-Oncogene Protein c-fli-1 - metabolism
RNA-Binding Protein EWS - genetics
RNA-Binding Protein EWS - metabolism
Sarcoma
Sarcoma, Ewing - genetics
Sarcoma, Ewing - metabolism
Serine
Signal Transduction
Translocation
Tumors
Up-Regulation
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Summary:Ewing sarcoma is a bone malignancy driven by a translocation event resulting in the fusion protein EWS/FLI1 (EF). EF functions as an aberrant and oncogenic transcription factor that misregulates the expression of thousands of genes. Previous work has focused principally on determining important transcriptional targets of EF, as well as characterizing important regulatory partnerships in EF-dependent transcriptional programs. Less is known, however, about EF-dependent metabolic changes or their role in Ewing sarcoma biology. Therefore, the metabolic effects of silencing EF in Ewing sarcoma cells were determined. Metabolomic analyses revealed distinct separation of metabolic profiles in EF-knockdown versus control-knockdown cells. Mitochondrial stress tests demonstrated that knockdown of EF increased respiratory as well as glycolytic functions. Enzymes and metabolites in several metabolic pathways were altered, including serine synthesis and elements of one-carbon metabolism. Furthermore, phosphoglycerate dehydrogenase (PHGDH) was found to be highly expressed in Ewing sarcoma and correlated with worse patient survival. PHGDH knockdown or pharmacologic inhibition caused impaired proliferation and cell death. Interestingly, PHGDH modulation also led to elevated histone expression and methylation. These studies demonstrate that the translocation-derived fusion protein EF is a master regulator of metabolic reprogramming in Ewing sarcoma, diverting metabolites toward biosynthesis. As such, these data suggest that the metabolic aberrations induced by EF are important contributors to the oncogenic biology of these tumors. This previously unexplored role of EWS/FLI1-driven metabolic changes expands the understanding of Ewing sarcoma biology, and has potential to significantly inform development of therapeutic strategies. .
ISSN:1541-7786
1557-3125
DOI:10.1158/1541-7786.mcr-17-0182