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Suppressing the Aberrant Transcriptional Functionality of EWS::FLI1 Oncoprotein by Designer polyQ Fusions with Its

Heng-Tong Duan1,2, Xiang-Le Zhang1,2, Lei-Lei Jiang1

  • 1Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.

Biomedicines
|February 27, 2026
PubMed

Insights

Researchers developed polyglutamine (polyQ) fusions to target the EWS::FLI1 oncoprotein in Ewing sarcoma. These fusions sequester EWS::FLI1, reducing its availability and altering downstream gene expression, offering a potential new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Ewing sarcoma is driven by the EWS::FLI1 oncoprotein, a chimeric transcription factor causing aberrant gene regulation.
  • Targeting EWS::FLI1 is crucial for suppressing oncogenic progression, but its inhibition and clearance present significant challenges.
  • Current therapeutic strategies require novel approaches to directly address EWS::FLI1's oncogenic functions.

Purpose of the Study:

  • To investigate the efficacy of a polyglutamine (polyQ) fusion strategy for directly targeting and suppressing EWS::FLI1.
  • To design and construct novel polyQ fusion proteins capable of sequestering EWS::FLI1 within Ewing sarcoma cells.
  • To evaluate the impact of these polyQ fusions on EWS::FLI1 cellular availability and downstream gene expression.

Main Methods:

  • A polyglutamine (polyQ) fusion strategy was employed using polyQ-expanded ataxin-7 (Atx793Q-N172) as a template.
  • Three distinct polyQ fusion proteins (Atx793Q-N172-SYGQ1, Atx793Q-N172-SYGQ2, Atx793Q-N172-LCD) were designed and constructed.
  • Experiments involved supernatant/pellet fractionation and immunofluorescence imaging in A673 Ewing sarcoma cells.

Main Results:

  • The designed polyQ fusion proteins successfully co-precipitated and co-localized with endogenous EWS::FLI1 in A673 cells.
  • PolyQ fusions sequestered EWS::FLI1 into insoluble aggregates, significantly reducing its soluble cellular availability.
  • The Atx793Q-N172-LCD fusion notably altered EWS::FLI1 downstream gene expression, increasing P21 (CDKN1A) and decreasing c-Myc.

Conclusions:

  • Engineered polyQ fusions effectively entrap endogenous EWS::FLI1 protein into aggregates, reducing its functional soluble fraction in Ewing sarcoma cells.
  • This sequestration strategy presents a novel approach to inhibit the oncogenic activity of EWS::FLI1.
  • The study offers a potential alternative therapeutic avenue for Ewing sarcoma and other cancers driven by similar oncogenic proteins.
Keywords:
EWS::FLI1Ewing sarcomaoncogenic proteinpolyQ fusionprotein aggregationsequestration

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