Journal Article

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

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

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/105 / 38/91 / 45/43 / 631/67/2332 / 631/67/395 / 64/60 / Acetylation / Animal models / Animals / Apoptosis / Bone Neoplasms - drug therapy / Bone Neoplasms - genetics / Bone Neoplasms - metabolism / Bone Neoplasms - pathology / Cancer / Cell Biology / Cell Line, Tumor / Development and progression / DNA damage / Doxorubicin / Doxorubicin - pharmacology / Drug therapy / E1A-Associated p300 Protein - genetics / E1A-Associated p300 Protein - metabolism / Enzyme inhibitors / Enzymes / Ewing's sarcoma / Ewings sarcoma / Female / FLI-1 protein / FLI1 protein / Fusion protein / Gene expression / Gene Expression Regulation, Neoplastic / Genetic aspects / Health aspects / Histone Deacetylase 6 - antagonists & inhibitors / Histone Deacetylase 6 - genetics / Histone Deacetylase 6 - metabolism / Histone Deacetylase Inhibitors - pharmacology / Human Genetics / Humans / Hydrolases / Internal Medicine / Medical prognosis / Medicine / Medicine & Public Health / Mice / Oncogene Proteins, Fusion - genetics / Oncogene Proteins, Fusion - metabolism / Oncogenes / Oncology / Oncology, Experimental / Patients / Promoter Regions, Genetic - genetics / Promoters (Genetics) / Proto-Oncogene Protein c-fli-1 - genetics / Proto-Oncogene Protein c-fli-1 - metabolism / RNA-Binding Protein EWS - genetics / RNA-Binding Protein EWS - metabolism / Sarcoma, Ewing - drug therapy / Sarcoma, Ewing - genetics / Sarcoma, Ewing - metabolism / Sarcoma, Ewing - pathology / Sp1 protein / Sp1 Transcription Factor - genetics / Sp1 Transcription Factor - metabolism / Tumor cell lines / Tumorigenesis / Xenograft Model Antitumor Assays / Xenografts / Young adults