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

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...

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Bibliographic Details
Published in:Oncogene 2021-09, Vol.40 (39), p.5843-5853
Main Authors: 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
Format: Article
Language:English
Subjects:
Acetylation
Animal models
Cancer
Carcinogenesis
Development and progression
DNA damage
Doxorubicin
Drug therapy
Enzyme inhibitors
Enzymes
Ewing's sarcoma
Ewings sarcoma
FLI-1 protein
FLI1 protein
Fusion protein
Gene expression
Genetic aspects
Health aspects
Histone Deacetylase 6
Humans
Hydrolases
Medical prognosis
Oncogenes
Oncology, Experimental
Patients
Promoter Regions, Genetic
Promoters (Genetics)
Proto-Oncogene Protein c-fli-1
Sarcoma, Ewing
Sp1 protein
Tumor cell lines
Tumorigenesis
Xenografts
Young adults
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Summary: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.
ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-021-01974-4