期刊
ONCOGENE
卷 40, 期 39, 页码 5843-5853出版社
SPRINGERNATURE
DOI: 10.1038/s41388-021-01974-4
关键词
-
资金
- Asociacion Espanola Contra el Cancer (AECC)
- Ministry of Science of Spain-FEDER (CIBERONC) [PI1700464, PI2000003, RD06/0020/0059]
- CIBERONC [CB16/12/00361]
- Consejeria de Salud, Junta de Andalucia [PI-0197-2016, PI-0013-2018, ECAI F2-0012-2018]
The study reveals that HDAC6 plays a regulatory role in EWS, and selective inhibition of HDAC6 can reduce the oncogenic functions of EWSR1-FLI1. High expression of HDAC6 is associated with poor prognosis in EWS patients, and a combination treatment of HDAC6 and doxorubicin significantly inhibits tumor growth in EWS models.
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.
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