Oncogenic partnerships: EWS-FLI1 protein interactions initiate key pathways of Ewing's sarcoma

Abstract

Targeted therapy for cancer, which is specifically directed toward the cancer without any potential for effects outside of controlling the tumor, is a gold standard for treatment. Ewing's sarcoma contains the potential target EWS-FLI1, as a result of a pathognomonic chromosomal translocation. The EWS-FLI1 fusion protein includes the EWS domain, a potent transcriptional activator alongside the highly conserved FLI1 ets DNA-binding domain. Because of the combination of these domains, the EWS-FLI1 fusion protein acts as an aberrant transcription factor whose expression results in cellular transformation. EWS-FLI1 functions by binding to normal cellular protein partners in transcription and splicing, similar to how a virus would corrupt normal cellular machinery for virion production. Therefore, understanding the protein-protein interactions of EWS-FLI1 and the pathways that are regulated by these partnerships will inform both oncogenesis and therapeutics. This review describes the known protein partners and transcriptional targets of EWS-FLI1, while proposing strategies for exploiting these partnerships with targeted therapy.

Fig. 1

EWS-FLI1 partners with multiple proteins that regulate mRNA transcription and splicing. A, EWS-FLI1 protein-protein interaction partners in transcription. EWS-FLI1 interacts with hsRBP7, RHA, BARD1, C-JUN, SAP1a, CBP/p300. The name of the gene product is listed below the interaction when a given complex is directly linked to that promoter. All references were reviewed that contained evidence of partner proteins for EWS-FLI1 and included if they contained at least two independent validation experiments. The description of each protein interaction is described in the text. Dotted lines indicate well-documented interactions between proteins described in models that did not specifically include EWS-FLI1. B, EWS-FLI1 protein-protein interaction partners in splicing. U1C and SF1 proteins interact with EWS-FLI1 to modulate splicing. Interactions with YB1 and SR inhibit or alter splicing. Dotted lines indicate well-documented interactions between proteins described in models that did not specifically include EWS-FLI1.