Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma
Autor: | Jaume Mora, María José Robles, Nabil Hajji, Antonio Llombart-Bosch, Ana M. Espinosa-Oliva, Katia Scotlandi, Giovanna Magagnoli, Rocío M. de Pablos, Angel M. Carcaboso, Eduardo Andrés-León, Laura Carmen Terrón-Camero, Daniel J. García-Domínguez, Sara Sanchez-Molina, Elisabet Figuerola-Bou, Rocío Flores-Campos, Lourdes Hontecillas-Prieto, Enrique de Álava, Isidro Machado, Guillem Pascual-Pasto |
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Přispěvatelé: | Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), Junta de Andalucía, European Commission, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica, Ministerio de Ciencia e Innovación (MICIN). España |
Rok vydání: | 2021 |
Předmět: |
Cancer Research
Carcinogenesis Sarcoma Ewing Biology medicine.disease_cause Histone Deacetylase 6 Article Fusion gene Paediatric cancer Downregulation and upregulation Genetics medicine Humans Doxorubicin Promoter Regions Genetic Molecular Biology Activator (genetics) Proto-Oncogene Protein c-fli-1 Acetylation Oncogenes medicine.disease Tumor progression FLI1 Cancer research Sarcoma medicine.drug |
Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname idUS. Depósito de Investigación de la Universidad de Sevilla Oncogene Digital.CSIC: Repositorio Institucional del CSIC Consejo Superior de Investigaciones Científicas (CSIC) |
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. Research in the E.D.A. lab is supported by Asociación Española Contra el Cáncer (AECC), the Ministry of Science of Spain-FEDER (CIBERONC, PI1700464, PI2000003, RD06/0020/0059)S. D.G.D. and L.H.P. are supported by CIBERONC (CB16/12/00361). D.G.D., M.J.R. and L.H.P. are PhD researchers funded by the Consejería de Salud, Junta de Andalucía (PI-0197-2016, ECAI F2-0012-2018 and PI-0013-2018, respectively). |
Databáze: | OpenAIRE |
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