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

Parrish, Janet K.; McCann, Tyler; Sechler, Marybeth; Sobral, Lays Martin; Ren, Wendan; Jones, Kenneth L.; Tan, Aik Choon; Jedlicka, Paul

doi:10.18632/oncotarget.26011

Cited by 37 publications

(36 citation statements)

References 58 publications

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“…8B). This inhibitory effect of JIB-04 on colony formation potential has been reported in other cancer types such as glioblastoma [21,26], lung [25], and Ewing sarcoma [31].…”

Section: The Effect Of Siepha2 Complexes Co-administered With Jib-04 supporting

confidence: 73%

Development of EphA2 siRNA-loaded lipid nanoparticles and combination with a small-molecule histone demethylase inhibitor in prostate cancer cells and tumor spheroids

Oner

Kotmakçı

Baird

et al. 2020

Preprint

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Background: siRNAs hold a great potential for cancer therapy, however, poor stability in body fluids and low cellular uptake limit their use in the clinic. To enhance the bioavailability of siRNAs in tumors, novel, safe, and effective carriers are needed. Results: Here, we developed cationic solid lipid nanoparticles (cSLNs) to carry siRNAs targeting EphA2 receptor tyrosine kinase (siEphA2), which is overexpressed in many solid tumors including prostate cancer (PCa). Using DDAB cationic lipid instead of DOTMA reduced nanoparticle size and enhanced both cellular uptake and gene silencing in PCa cells. DDAB-cSLN showed better cellular uptake efficiency with similar silencing compared to commercial transfection reagent Dharmafect-2. After verifying the efficacy of siEphA2-loaded nanoparticles, we further evaluated a potential combination with a histone lysine demethylase inhibitor, JIB-04. Silencing EphA2 by siEphA2-loaded DDAB-cSLN did not affect the viability (2D and 3D), migration, and clonogenicity of PC-3 cells alone. However, upon co-administration, there was a decrease in the aforementioned cellular responses due to JIB-04. Furthermore, JIB-04 decreased EphA2 expression, and thus, silencing efficiency of siEphA2-loaded nanoparticles was further increased with co-treatment. Conclusions: We have successfully developed a novel siRNA-loaded lipid nanoparticle for targeting EphA2. Moreover, detailed preliminary results of the effects of JIB-04, alone and in combination with siEphA2, on PCa cells and tumor spheroids were presented for the first time. Our delivery system provides high transfection efficiency and shows a great promise for targeting other genes and cancer types in further in vitro and in vivo studies.

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“…8B). This inhibitory effect of JIB-04 on colony formation potential has been reported in other cancer types such as glioblastoma [21,26], lung [25], and Ewing sarcoma [31].…”

Section: The Effect Of Siepha2 Complexes Co-administered With Jib-04 supporting

confidence: 73%

Development of EphA2 siRNA-loaded lipid nanoparticles and combination with a small-molecule histone demethylase inhibitor in prostate cancer cells and tumor spheroids

Oner

Kotmakçı

Baird

et al. 2020

Preprint

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“…Specific pharmacologic inhibitors of KDM3A do not exist at this time. However, our recent studies demonstrated growth-inhibitory activity of a pan-JHDM inhibitor (JIB-04 [19]), in Ewing Sarcoma [20]. To determine whether JIB-04 also inhibits the growth of RMS cells, we examined its effects in the clonogenic assay.…”

Section: The Pan-jhdm Pharmacologic Inhibitor Jib-04 Potently Inhibitmentioning

confidence: 99%

KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma

et al. 2020

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Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy of childhood. RMS exists as two major disease subtypes, with oncofusion-positive RMS (FP-RMS) typically carrying a worse prognosis than oncofusion-negative RMS (FN-RMS), in part due to higher propensity for metastasis. Epigenetic mechanisms have recently emerged as critical players in the pathogenesis of pediatric cancers, as well as potential new therapeutic vulnerabilities. Herein, we show that the epigenetic regulator KDM3A, a member of the Jumonji-domain histone demethylase (JHDM) family, is overexpressed, potently promotes colony formation and transendothelial invasion, and activates the expression of genes involved in cell growth, migration and metastasis, in both FN-RMS and FP-RMS. In mechanistic studies, we demonstrate that both RMS subtypes utilize a KDM3A/Ets1/MCAM disease-promoting axis recently discovered in Ewing Sarcoma, another aggressive pediatric cancer of distinct cellular and molecular origin. We further show that KDM3A depletion in FP-RMS cells inhibits both tumor growth and metastasis in vivo, and that RMS cells are highly sensitive to colony growth inhibition by the pan-JHDM inhibitor JIB-04. Together, our studies reveal an important role for the KDM3A/Ets1/MCAM axis in pediatric sarcomas of distinct cellular and molecular ontogeny, and identify new targetable vulnerabilities in RMS.

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“…Furthermore, acting directly, and through induction of expression of the Ets1 transcription factor, KDM3A upregulates expression of the cell surface protein MCAM, resulting in increased cell motility and metastasis 60 . Ewing Sarcoma cells are also highly sensitive to the pan-JHDM pharmacologic inhibitor JIB-04 61 .…”

Section: Kdm3mentioning

confidence: 99%

Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview

McCann

Sobral

Self

et al. 2019

Expert Opinion on Therapeutic Targets

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Introduction: Epigenetic mechanisms of gene regulatory control play fundamental roles in developmental morphogenesis, and, as more recently appreciated, are heavily implicated in the onset and progression of neoplastic disease, including cancer. Many epigenetic mechanisms are therapeutically targetable, providing additional incentive for understanding of their contribution to cancer and other types of neoplasia.

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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

Cited by 37 publications

References 58 publications

Development of EphA2 siRNA-loaded lipid nanoparticles and combination with a small-molecule histone demethylase inhibitor in prostate cancer cells and tumor spheroids

Development of EphA2 siRNA-loaded lipid nanoparticles and combination with a small-molecule histone demethylase inhibitor in prostate cancer cells and tumor spheroids

KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma

Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview

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