Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma

Autor: García-Domínguez DJ, Hajji N, Sánchez-Molina S, Figuerola-Bou E, de Pablos RM, Espinosa-Oliva AM, Andrés-León E, Terrón-Camero LC, Flores-Campos R, Pascual-Pastó G, Robles MJ, Machado I, Llombart-Bosch A, Magagnoli G, Scotlandi K, Carcaboso AM, Mora J, de Álava E, Hontecillas-Prieto L
Rok vydání: 2021
Zdroj: Oncogene
r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
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ISSN: 0950-9232
Popis: 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.
Databáze: OpenAIRE
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