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

Ewing sarcoma (EWS) is an aggressive developmental sarcoma driven by a fusion gene, EWSR1-FLI1. However, little is known about the regulation of EWSR1-FLI1 chimeric fusion gene expression. Here, we demonstrate that active nuclear HDAC6 in EWS modulates acetylation status of specificity protein 1 (SP1), consequently regulating SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of 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. Overexpression of HDAC6 in primary EWS tumor clinical samples correlates with a poor prognosis. Notably, a combination treatment of a selective HDAC6 inhibitor and doxorubicin (standard of care in EWS) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for EWS patients.