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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

ABSTRACT: The overall goal of this study was to characterize the activity and mechanism(s) of action of the pan-Jumonji domain histone demethylase small molecule inhibitor JIB-04 in the pediatric bone and soft tissue cancer Ewing Sarcoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE119832 | GEO | 2019/01/03

REPOSITORIES: GEO

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RNAseq of Plasmodium falciparum 3D7 parasites treated with the Jumonji pan inhibitor JIB-04

Project description:Little is known about the role of the three Jumonji C (JmjC) enzymes in Plasmodium falciparum (Pf). Here, we show that JIB-04 and other established inhibitors of mammalian JmjC histone demethylases kill asexual blood stage parasites and are even more potent at blocking gametocyte development and gamete formation. In late stage parasites, JIB-04 increased levels of trimethylated lysine residues on histones, suggesting the inhibition of P. falciparum Jumonji demethylase activity. These epigenetic defects coincide with deregulation of invasion, cell motor, and sexual development gene programs, including gene targets coregulated by the PfAP2-I transcription factor and chromatin-binding factor, PfBDP1. Mechanistically, we demonstrate that PfJmj3 converts 2-oxoglutarate to succinate in an iron-dependent manner consistent with mammalian Jumonji enzymes, and this catalytic activity is inhibited by JIB-04 and other Jumonji inhibitors. Our pharmacological studies of Jumonji activity in the malaria parasite provide evidence that inhibition of these enzymatic activities is detrimental to the parasite.

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Global transcriptional response of P. falciparum NF54 early gametocytes treated with the Jumonji histone demethylase inhibitor JIB-04

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Identification of genes modulated by JIB-04 in lung cancer cells

Project description:JIB-04 is an inhibitor of Jumonji histone demethylases identified through a cell based screen that measures the reactivation of an epigenetically silenced transgene. The active JIB-04 E-isomer shows selectivity for cancer vs. normal cells affecting both transcriptional patterns and cell viability in a cancer specific manner. H358 lung cancer cells or the patient matched HCC4017 (cancer) vs. HBEC30KT (immortalized normal) lung cell pair were treated with DMSO vehicle or 500nM E-isomer or 500 nM Z-isomer of JIB-04 for 4 h or 24 h and RNA extracted.

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Identification of genes modulated by JIB-04 in lung cancer cells

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Transcriptome analysis by RNA sequencing after treatment with JIB-04 in hepatocellular carcinoma

Project description:Our RNA sequencing analysis revealed that the JIB-04 treatment altered the expression of genes that are involved in the cell cycle, p53 signaling pathway, and apoptosis, and are also related to several cancers including hepatocellular carcinoma. JIB-04 also altered the expression of genes involved in various signaling pathways such as the FoxO signaling pathway, the PI3K-Akt signaling pathway, which is crucial for the proliferation and maintenance of hepatocellular carcinoma cells.

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Transcriptome analysis by RNA sequencing after treatment with JIB-04 in colorectal cancer

Project description:We investigate RNA sequencing analysis revealed that the JIB-04 treatment altered the expression of genes that are involved in the cell cycle, apoptosis, and DNA replication and are also related to several cancers including colorectal cancer. JIB-04 also altered the expression of genes involved in various signaling pathways such as the MAPK signaling pathway, the PI3K-Akt signaling pathway, and the Wnt signaling pathway, which is crucial for the proliferation and maintenance of colorectal cancer cells.

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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.

Project description: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.

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Project description:Measuring the effects of the compound JIB-04 on global transcription, NFkB pathway-related genes, and integrated HIV proviral DNA.

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Project description: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

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