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.

中文翻译：

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HDAC6通过尤文氏肉瘤中的EWSR1启动子调节致癌驱动因子EWSR1-FLI1的表达

尤因肉瘤（EWS）是一种由融合基因EWSR1-FLI1驱动的侵袭性发展肉瘤。但是，关于EWSR1-FLI1嵌合融合基因表达的调控知之甚少。在这里，我们证明EWS中的活性核HDAC6调节特异性蛋白1（SP1）的乙酰化状态，从而调节SP1 / P300激活物复合物与EWSR1和EWSR1-FLI1启动子的结合。HDAC6的选择性抑制会削弱激活剂复合物SP1 / P300的结合，从而诱导EWSR1-FLI1下调并显着降低其致癌功能。另外，EWS细胞系对HDAC6抑制的敏感性高于其他肿瘤或非肿瘤细胞系。HDAC6在原发性EWS肿瘤临床样品中的过表达与预后不良有关。值得注意的是 在两种EWS鼠异种移植模型中，选择性HDAC6抑制剂和阿霉素（EWS的护理标准）的联合治疗可显着抑制肿瘤的生长。这些结果可能为EWS患者带来合适且有希望的治疗替代方案。