The Jumonji-domain histone demethylase inhibitor JIB-04 deregulates oncogenic programs and increases DNA damage in Ewing Sarcoma, resulting in impaired cell proliferation and survival, and reduced tumor growth
Ewing Sarcoma is definitely an aggressive malignant neoplasm affecting children and youthful adults. Ewing Sarcoma is driven by transcription factor fusion oncoproteins, most generally EWS/Fli1. Although some patients is often curable rich in-dose, multi-agent, chemotherapy, individuals that can’t presently have couple of options. Targeting from the driver oncofusion remains may well therapeutic approach, but has shown difficult. Recent work has pointed to epigenetic mechanisms as key players, and potential new therapeutic targets, in Ewing Sarcoma. Within this study we examined the game from the pan-JHDM pharmacologic inhibitor JIB-04 within this disease. We reveal that JIB-04 potently inhibits the development and viability of Ewing Sarcoma cells, as well as impairs tumor xenograft growth. Effects on histone methylation at growth-inhibitory doses vary among cell lines, with many cell lines exhibiting elevated total H3K27me3 levels, and a few elevated H3K4me3 and H3K9me3. JIB-04 treatment broadly alters expression of oncogenic and tumor suppressive pathways, including downregulation of known oncogenic people from the Homeobox B and D clusters.
JIB-04 also disrupts the EWS/Fli1 expression signature, including downregulation of professional-proliferative pathways normally under positive oncofusion control. Interestingly, these changes are supported by elevated quantity of a EWS/Fli1 oncofusion, suggesting the drug might be uncoupling EWS/Fli1 from the oncogenic JIB-04 program. All Ewing Sarcoma cell lines examined also manifest elevated DNA damage upon JIB-04 treatment. Together, the findings claim that JIB-04 functions via multiple mechanisms to compromise Ewing Sarcoma cell growth and viability.