Article
Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma
Author/s | García-Domínguez, Daniel J.
![]() ![]() ![]() ![]() ![]() ![]() Hajji, Nabil Sánchez Molina, Sara Figuerola Bou, Elisabet Martínez de Pablos, Rocío ![]() ![]() ![]() ![]() ![]() ![]() ![]() Espinosa Oliva, Ana María ![]() ![]() ![]() ![]() ![]() ![]() ![]() Flores Campos, Rocío Robles Frías, María José Álava Casado, Enrique de ![]() ![]() ![]() ![]() ![]() ![]() ![]() Hontecillas Prieto, Lourdes |
Department | Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica |
Publication Date | 2021 |
Deposit Date | 2022-06-08 |
Published in |
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Abstract | 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 ... 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. |
Funding agencies | Ministerio de Ciencia e Innovación (MICIN). España Junta de Andalucía |
Project ID. | PI1700464
![]() PI2000003 ![]() RD06/0020/0059 ![]() PI-0197-2016 ![]() ECAI F2-0012-2018 ![]() PI-0013-2018 ![]() |
Citation | García-Domínguez, D.J., Hajji, N., Sánchez Molina, S., Figuerola Bou, E., Martínez de Pablos, R., Espinosa Oliva, A.M.,...,Hontecillas Prieto, L. (2021). Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma. Oncogene, 40 (39), 5843-5853. https://doi.org/10.1038/s41388-021-01974-4. |
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