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bioRxiv · 10.1101/2023.01.24.524910

KDM6 demethylases mediate EWSR1-FLI1-driven oncogenic transformation in Ewing Sarcoma

Figuerola-Bou, E.·Rios-Astorch, C.·Blanco, E.·Sanchez-Jimenez, M.·Taboas, P.·Fernandez, G.·Gomez, S.·Munoz, O.·Castellano-Escuder, P.·Perez-Jaume, S.·Prada, E.·Mateo-Lozano, S.·Riggi, N.·Avgustinova, A.·Lavarino, C.·Di Croce, L.·Sanchez-Molina, S.·Mora, J.
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Abstract

Ewing Sarcoma (EwS) is an aggressive bone and soft tissue tumor driven by the fusion oncoprotein EWSR1-FLI1. This aberrant transcription factor binds to GGAA microsatellites, causing epigenetic reprogramming through the formation of active neo-enhancers in a permissive cellular context. Inhibition of the oncogene remains challenging and current efforts instead seek to exploit emergent epigenetic treatments targeting EWSR1-FLI1 cofactors. Here, stemming from the genome-wide redistribution of H3K27me3 upon expression of EWSR1-FLI1 in pediatric hMSC, we unravel the contribution of the H3K27me3 demethylases KDM6A and KDM6B in transcriptional activation at EWSR1-FLI1 enhancers. We found that KDM6A has a demethylase-independent role in recruiting the SWI/SNF member BRG1 at EWSR1-FLI1-primed enhancers containing single GGAA motif, which is critical for EwS tumor growth. Conversely, KDM6B demethylates H3K27me3 at EWSR1-FLI1-active enhancers containing multimeric GGAA repeats and its deletion synergizes with EZH2 inhibitors. Our results highlight KDM6 demethylases as EWSR1-FLI1 cofactors with potential for future targeted therapies.

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Figuerola-Bou, E., Rios-Astorch, C., Blanco, E., Sanchez-Jimenez, M., Taboas, P., Fernandez, G., Gomez, S., Munoz, O., Castellano-Escuder, P., Perez-Jaume, S., Prada, E., Mateo-Lozano, S., Riggi, N., Avgustinova, A., Lavarino, C., Di Croce, L., Sanchez-Molina, S., Mora, J.. 2023-01-24. KDM6 demethylases mediate EWSR1-FLI1-driven oncogenic transformation in Ewing Sarcoma. https://doi.org/10.1101/2023.01.24.524910

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