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Fusion protein EWS‐FLI1 partners with EWSR1 to regulate transcription in Ewing sarcoma
Author(s) -
Ahmed Nasiha,
Schwartz Jacob
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06029
Subject(s) - fli1 , sarcoma , fusion protein , transcription factor , biology , cancer research , transcription (linguistics) , fusion gene , chromosomal translocation , pediatric cancer , oncogene proteins , ewing's sarcoma , microbiology and biotechnology , cancer , gene , genetics , medicine , regulation of gene expression , pathology , recombinant dna , linguistics , philosophy
Chromosomal translocation events drive many types of pediatric cancers. Ewing sarcoma is a pediatric bone cancer driven by a chromosomal translocation where the N‐terminal low‐complexity domain of EWSR1 fuses to the DNA‐binding domain of the ETS transcription factor FLI1. This fusion creates the aberrant transcription factor EWS‐FLI1, which drives tumor formation by altering the transcriptional landscape. Interestingly, constitutive expression of EWSR1 is retained in Ewing sarcoma cells. The low‐complexity domain found in EWSR1 and EWS‐FLI1 is intrinsically‐disordered and can mediate protein‐protein interactions with itself and other protein partners. Moreover, this domain has the propensity to phase separate. Despite the common domain between the two proteins, very little is known about the effect of EWSR1 on EWS‐FLI1 activity. We performed RNA‐sequencing to reveal that EWSR1 and EWS‐FLI1 coregulate a large pool of genes in Ewing sarcoma cells. Loss of EWSR1 in inhibits anchorage‐independent growth, suggesting that EWSR1 plays a role in cancerous properties of Ewing sarcoma cells. We have shown EWSR1 and EWS‐FLI1 bind each other directly in vitro and in vivo. Finally, we have found the existence of EWSR1, EWS‐FLI1, and RNA Pol II in a novel granular body in Ewing sarcoma cell lines. This direct interaction of EWSR1 and EWS‐FLI1 presents a straight‐forward model that merges wild‐type and fusion properties to alter transcriptional output and drive Ewing sarcoma biology. Support or Funding Information National Institutes of Health, American Cancer Society