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

Oncotarget
J K ParrishPaul Jedlicka

Abstract

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 positi...Continue Reading

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Citations

Feb 14, 2019·Expert Opinion on Therapeutic Targets·Tyler S McCannPaul Jedlicka
Jul 6, 2019·Frontiers in Oncology·Dana L CaseyNai-Kong V Cheung
Jun 25, 2020·Genes & Cancer·Lays Martin SobralPaul Jedlicka
Jul 17, 2020·Frontiers in Oncology·Anthony QuaglianoSonali P Barwe

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Methods Mentioned

BETA
RNA-seq
ChIP-PCR
ChIP-seq
flow cytometry
xenografts
xenograft
Flow
Assay
immunoprecipitation

Software Mentioned

GSEA
Cufflinks
gSNAP
DAVID
DAVID ( NIH Database for Annotation , Visualization , and Inte...
Gene Set Enrichment Analysis ( GSEA
R
GraphPad

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