PRJNA673347
HDAC6 inhibition in Ewing sarcoma cell lines_RNA sequencing
Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor of children and young adults in which principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 in the regulation of oncogenesis, survival, and tumor progression processes has been highly describe, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in ES modulates SP1 acetylation status, consequently regulating the SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 disconnects the activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, the ES cell lines are highly sensitive to HDAC6 inhibition, to a greater extent than other tumor and non-tumor cell lines. High expression of HDAC6 in primary ES tumor samples from patients correlates with poor prognosis. Notably, a combination treatment of selective HDAC6i (ACY-1215) and doxorubicin (a DNA damage agent used in standard therapy of ES patients) dramatically inhibits tumor growth in two murine models. These results could lead to suitable and promising therapeutic alternatives for ES patients.