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.

Autor:	Parrish JK; Department of Pathology, Anschutz Medical Campus, Aurora, CO, USA.; University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., McCann TS; Department of Pathology, Anschutz Medical Campus, Aurora, CO, USA.; University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Sechler M; Cancer Biology Graduate Training Program, Anschutz Medical Campus, Aurora, CO, USA.; University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Sobral LM; Department of Pathology, Anschutz Medical Campus, Aurora, CO, USA.; University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Ren W; Department of Medicine, Anschutz Medical Campus, Aurora, CO, USA.; University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Jones KL; Department of Pediatrics, Anschutz Medical Campus, Aurora, CO, USA.; University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Tan AC; Cancer Biology Graduate Training Program, Anschutz Medical Campus, Aurora, CO, USA.; Department of Medicine, Anschutz Medical Campus, Aurora, CO, USA.; University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Jedlicka P; Department of Pathology, Anschutz Medical Campus, Aurora, CO, USA.; Cancer Biology Graduate Training Program, Anschutz Medical Campus, Aurora, CO, USA.; University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2018 Sep 04; Vol. 9 (69), pp. 33110-33123. Date of Electronic Publication: 2018 Sep 04 (Print Publication: 2018).
DOI:	10.18632/oncotarget.26011
Abstrakt:	Ewing Sarcoma is an aggressive malignant neoplasm affecting children and young adults. Ewing Sarcoma is driven by transcription factor fusion oncoproteins, most commonly EWS/Fli1. While some patients can be cured with high-dose, multi-agent, chemotherapy, those that cannot currently have few options. Targeting of the driver oncofusion remains a logical therapeutic approach, but has proven difficult. Recent work has pointed to epigenetic mechanisms as key players, and potential new therapeutic targets, in Ewing Sarcoma. In this study we examined the activity of the pan-JHDM pharmacologic inhibitor JIB-04 in this disease. We show that JIB-04 potently inhibits the growth and viability of Ewing Sarcoma cells, and also impairs tumor xenograft growth. Effects on histone methylation at growth-inhibitory doses vary among cell lines, with most cell lines exhibiting increased total H3K27me3 levels, and some increased H3K4me3 and H3K9me3. JIB-04 treatment widely alters expression of oncogenic and tumor suppressive pathways, including downregulation of known oncogenic members of the Homeobox B and D clusters. JIB-04 also disrupts the EWS/Fli1 expression signature, including downregulation of pro-proliferative pathways normally under positive oncofusion control. Interestingly, these changes are accompanied by increased levels of the EWS/Fli1 oncofusion, suggesting that the drug could be uncoupling EWS/Fli1 from its oncogenic program. All Ewing Sarcoma cell lines examined also manifest increased DNA damage upon JIB-04 treatment. Together, the findings suggest that JIB-04 acts via multiple mechanisms to compromise Ewing Sarcoma cell growth and viability. Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu