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

Abstract

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.

Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation

“…HDAC6 is widely expressed across tissues in the body 38 . In cancer, HDAC6 is overexpressed and known to correlate with poor prognosis 99 , 100 . Here, we observed that HDAC6 expression is increased in mdx mice, which indicates that it could participate in the DMD pathology.…”

Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance

“…HDAC6 was reported to increase the level of the Ewing sarcoma breakpoint region 1 fusion gene (EWSR1-FLI1) [ 21 ]. A high level of HDAC6 can predict low survival of patients with Ewing Sarcoma [ 21 ].…”

“…HDAC6 was reported to increase the level of the Ewing sarcoma breakpoint region 1 fusion gene (EWSR1-FLI1) [ 21 ]. A high level of HDAC6 can predict low survival of patients with Ewing Sarcoma [ 21 ]. HDAC6 was shown to promote the invasion and migration of rhabdomyosarcoma (RMS) cells via RAC1, a Rho family GTPase [ 22 ].…”

Ewing Sarcoma Meets Epigenetics, Immunology and Nanomedicine: Moving Forward into Novel Therapeutic Strategies

“…A screening of 43 epigenetic drugs revealed that the most sensitive agents in EWS cell lines were related to HDAC inhibition, being BML-281, a specific inhibitor of HDAC6, the drug with the lower IC50. BML-281 increased acetylation levels of specificity protein 1 (SP1), reducing its binding to the EWSR1-FLI1 promoter and causing repression of the oncogene and its associated targets [ 48 ]. Furthermore, the combination of the HDAC6 inhibitor ACY-1215 with doxorubicin reduced tumor growth in EWS xenografts [ 48 ].…”

“…BML-281 increased acetylation levels of specificity protein 1 (SP1), reducing its binding to the EWSR1-FLI1 promoter and causing repression of the oncogene and its associated targets [ 48 ]. Furthermore, the combination of the HDAC6 inhibitor ACY-1215 with doxorubicin reduced tumor growth in EWS xenografts [ 48 ]. On the other hand, HDAC1 and HDAC2 knockouts demonstrated a reduction in invasiveness and tumor growth in xenografts [ 49 ].…”