ArticleCancer research2025
KDM6 Demethylases Contribute to EWSR1::FLI1-Driven Oncogenic Reprogramming in Ewing Sarcoma.
Article in Cancer research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
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Who cites it
2 citing papers in PubMed.
- Review
- Circuitous Ways of EWS::FLI1 Using Circular RNA ZNF609 to Evade Translational Repression by miR-145 in Ewing's Sarcoma.Biomedicines · 2026Article
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Authors and funding
19 authors.
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Abstract
Ewing sarcoma is a highly aggressive tumor arising in bones and soft tissues, driven by the fusion oncoprotein EWSR1::FLI1. This aberrant transcription factor binds to GGAA microsatellites, causing epigenetic reprogramming through the formation of active neoenhancers in a permissive cellular context. Inhibition of the oncogene remains challenging, and current efforts seek to exploit emergent epigenetic treatments targeting EWSR1::FLI1 cofactors. In Ewing sarcoma, neoenhancers are characterized by strong enrichment of the active H3K27ac mark and a concomitant lack of the repressive H3K27me3 mark. These regions are typically decorated with high levels of H3K27me3 prior to EWSR1::FLI1 activation. In this study, upon expression of EWSR1::FLI1 in human pediatric mesenchymal stem cells, considered the putative cell of origin of Ewing sarcoma, we unraveled the genome-wide redistribution of H3K27me3. Stemming from these results, we elucidated the contribution of the H3K27me3 demethylases KDM6A/UTX and KDM6B/JMJD3 in the transcriptional activity of EWSR1::FLI1-induced enhancers. KDM6A had a demethylase-independent role in recruiting BRG1 at EWSR1::FLI1-primed enhancers containing single GGAA motifs, which was critical for Ewing sarcoma tumor growth. Conversely, KDM6B demethylated H3K27me3 at specific EWSR1::FLI1-active enhancers, colocalizing with BRG1 at GGAA repeats. Loss of KDM6B impaired the growth of Ewing sarcoma tumor xenografts. These results highlight KDM6 demethylases as EWSR1::FLI1 functional partners with potential as targets for treating Ewing sarcoma. SIGNIFICANCE: KDM6A and KDM6B mediate critical mechanisms behind EWSR1::FLI1 transcriptional activation program involving demethylase-independent and dependent functions, respectively, supporting the development of therapeutic strategies targeting these demethylases in Ewing sarcoma.
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