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 de novo
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 in vitro 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.Implications: 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. Mol
Cancer Res; 15(11); 1517-30. ©2017 AACR.