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  • García-Domínguez, Daniel J; Hajji, Nabil; Sánchez-Molina, Sara; Figuerola-Bou, Elisabet; de Pablos, Rocío M; Espinosa-Oliva, Ana M; Andrés-León, Eduardo; Terrón-Camero, Laura Carmen; Flores-Campos, Rocío; Pascual-Pasto, Guillem; Robles, María José; Machado, Isidro; Llombart-Bosch, Antonio; Magagnoli, Giovanna; Scotlandi, Katia; Carcaboso, Ángel M; Mora, Jaume; de Álava, Enrique; Hontecillas-Prieto, Lourdes

    Oncogene, 09/2021, Volume: 40, Issue: 39
    Journal Article

    Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor of children and young adults in which the principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 protein in the regulation of oncogenesis, survival, and tumor progression processes has been described in-depth, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in EWS modulates the acetylation status of specificity protein 1 (SP1), consequently regulating the SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of the activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. High expression of HDAC6 in primary EWS tumor samples from patients correlates with a poor prognosis in two independent series accounting 279 patients. Notably, a combination treatment of a selective HDAC6 and doxorubicin (a DNA damage agent used as a standard therapy of EWS patients) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for patients with EWS.