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

Janet K. Parrish; Tyler S. McCann; Marybeth Sechler; Lays M. Sobral; Wenhua Ren; Kenneth L. Jones; Aik Choon Tan; Paul Jedlicka

doi:10.18632/oncotarget.26011

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

Janet K. Parrish, Tyler S. McCann, Marybeth Sechler, Lays M. Sobral, Wenhua Ren, Kenneth L. Jones, Aik Choon Tan, Paul Jedlicka

Research output: Contribution to journal › Article › peer-review

35 Citations (Scopus)

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, multiagent, 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.

Original language	English
Pages (from-to)	33110-33123
Number of pages	14
Journal	Oncotarget
Volume	9
Issue number	69
DOIs	https://doi.org/10.18632/oncotarget.26011
Publication status	Published - 2018 Sept 1

Bibliographical note

Funding Information:
Funding support for this work was provided by: the Cancer League of Colorado, the Mya Lin Terry and Make Some Noise Foundations, and R01-CA183874 (PJ); F31-CA203053 (MS); T32-CA190216 (TSM).

Funding Information:
We are grateful to Dr. Elisabeth Martinez at UT Southwestern Medical Center for providing samples of active (E isomer) and inactive (Z isomer) JIB-04, and for advice on compound handling and administration. We further wish to thank the following University of Colorado Cancer Center Core Facilities: Flow Cytometry, Small Animal Imaging, and Genomics and Bioinformatics (all supported by P30-CA046934). We also wish to thank Drs. Heide Ford and James Lambert for helpful discussions and critical reading of the manuscript.

Funding Information:
We are grateful to Dr. Elisabeth Martinez at UT Southwestern Medical Center for providing samples of active (E isomer) and inactive (Z isomer) JIB-04, and for advice on compound handling and administration. We further wish to thank the following University of Colorado Cancer Center Core Facilities: Flow Cytometry, Small Animal Imaging, and Genomics and Bioinformatics (all supported by P30-CA046934). We also wish to thank Drs. Heide Ford and James Lambert for helpful discussions and critical reading of the manuscript. Funding support for this work was provided by: the Cancer League of Colorado, the Mya Lin Terry and Make Some Noise Foundations, and R01-CA183874 (PJ); F31-CA203053 (MS); T32-CA190216 (TSM).

Publisher Copyright:
© Parrish et al.

Keywords

Demethylase
Epigenetics
Ewing Sarcoma
Inhibitor
Jumonji

ASJC Scopus subject areas

Oncology

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Parrish, J. K., McCann, T. S., Sechler, M., Sobral, L. M., Ren, W., Jones, K. L., Tan, A. C., & Jedlicka, P. (2018). 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, 9(69), 33110-33123. https://doi.org/10.18632/oncotarget.26011

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 S.; Sechler, Marybeth et al.
In: Oncotarget, Vol. 9, No. 69, 01.09.2018, p. 33110-33123.

Research output: Contribution to journal › Article › peer-review

Parrish, JK, McCann, TS, Sechler, M, Sobral, LM, Ren, W, Jones, KL, Tan, AC & Jedlicka, P 2018, '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, vol. 9, no. 69, pp. 33110-33123. https://doi.org/10.18632/oncotarget.26011

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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, multiagent, 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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author = "Parrish, {Janet K.} and McCann, {Tyler S.} and Marybeth Sechler and Sobral, {Lays M.} and Wenhua Ren and Jones, {Kenneth L.} and Tan, {Aik Choon} and Paul Jedlicka",

note = "Funding Information: Funding support for this work was provided by: the Cancer League of Colorado, the Mya Lin Terry and Make Some Noise Foundations, and R01-CA183874 (PJ); F31-CA203053 (MS); T32-CA190216 (TSM). Funding Information: We are grateful to Dr. Elisabeth Martinez at UT Southwestern Medical Center for providing samples of active (E isomer) and inactive (Z isomer) JIB-04, and for advice on compound handling and administration. We further wish to thank the following University of Colorado Cancer Center Core Facilities: Flow Cytometry, Small Animal Imaging, and Genomics and Bioinformatics (all supported by P30-CA046934). We also wish to thank Drs. Heide Ford and James Lambert for helpful discussions and critical reading of the manuscript. Funding Information: We are grateful to Dr. Elisabeth Martinez at UT Southwestern Medical Center for providing samples of active (E isomer) and inactive (Z isomer) JIB-04, and for advice on compound handling and administration. We further wish to thank the following University of Colorado Cancer Center Core Facilities: Flow Cytometry, Small Animal Imaging, and Genomics and Bioinformatics (all supported by P30-CA046934). We also wish to thank Drs. Heide Ford and James Lambert for helpful discussions and critical reading of the manuscript. Funding support for this work was provided by: the Cancer League of Colorado, the Mya Lin Terry and Make Some Noise Foundations, and R01-CA183874 (PJ); F31-CA203053 (MS); T32-CA190216 (TSM). Publisher Copyright: {\textcopyright} Parrish et al.",

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N2 - 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, multiagent, 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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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

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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