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Polycomb and KDM6A Roles in the Epigenetic Dynamics of Ewing Sarcoma Tumorigenesis

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Universitat de Barcelona. Facultat de Medicina

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[eng] Ewing sarcoma (ES) is a highly aggressive tumour of the bone and soft tissue that typically affects children, adolescents, and young adults. The fusion protein EWSR1‐FLI1 is the main genetic alteration found that acts as a pioneer factor during early ES tumorigenesis. EWSR1– FLI1 binds GGAA microsatellites causing remodelling of enhancers and genome reprogramming. Among the proteins cooperating with EWSR1‐FLI1 at enhancers, our group has described that the Polycomb subunit RING1B co‐localizes genome‐wide and promotes oncogene recruitment and transcriptional activation of key enhancer genes. In this thesis, we show that RING1B is a critical factor for ES tumour growth and, together with other E3 ubiquitin ligases, is deregulated by the neddylation pathway inhibitor MLN4924 (pevonedistat). Treatment of ES cell lines with the inhibitor promotes RING1B loss from EWSR1‐FLI1–activated targets as well as eviction of EWSR1‐FLI1, thereby deregulating gene expression. Lack of neddylation caused by the drug appears to be the mechanism behind the in vitro and in vivo degradation of RING1B. We also study how introduction of EWSR1‐FLI1 to a putative cell‐of‐origin deregulates distribution of the histone repressive mark H3K27me3. Although the global levels of this histone modification are maintained, we observe a perturbed distribution. Specifically, gain or loss of H3K27me3 occurs in some EWSR1‐FLI1–repressed or –activated regions, respectively, which coincide with enrichment of its writer, EZH2, and its eraser, KDM6A, in a transformed ES cell line. Finally, we demonstrate that targeting the tumorigenic distribution of H3K27me3 by combined inhibition of EZH2 (with GSK126) and KDM6A (with GSKJ4) causes a synergic cytotoxic response in ES cell lines. Altogether, our data provide further insight into the epigenetic mechanisms underlying EWSR1‐FLI1–mediated transformation and reveal new targets for future clinical trials.

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Polycomb and KDM6A Roles in the Epigenetic Dynamics of Ewing Sarcoma Tumorigenesis