Targeting histone demethylases in MYC-driven neuroblastomas with ciclopirox

Jun Yang; Sandra Milasta; Dongli Hu; Alaa M. AlTahan; Rodrigo B. Interiano; Junfang Zhou; Jesse Davidson; Jonathan Low; Wenwei Lin; Ju Bao; Pollyanna Goh; Amit C. Nathwani; Ruoning Wang; Yingdi Wang; Su Sien Ong; Vincent A. Boyd; Brandon Young; Sourav Das; Anang Shelat; Yinan Wu; Zhenmei Li; Jie J. Zheng; Ashutosh Mishra; Yong Cheng; Chunxu Qu; Junmin Peng; Douglas R. Green; Stephen White; R. Kiplin Guy; Taosheng Chen; Andrew M. Davidoff

doi:10.1158/0008-5472.CAN-16-0826

Targeting histone demethylases in MYC-driven neuroblastomas with ciclopirox

Jun Yang, Sandra Milasta, Dongli Hu, Alaa M. AlTahan, Rodrigo B. Interiano, Junfang Zhou, Jesse Davidson, Jonathan Low, Wenwei Lin, Ju Bao, Pollyanna Goh, Amit C. Nathwani, Ruoning Wang, Yingdi Wang, Su Sien Ong, Vincent A. Boyd, Brandon Young, Sourav Das, Anang Shelat, Yinan WuZhenmei Li, Jie J. Zheng, Ashutosh Mishra, Yong Cheng, Chunxu Qu, Junmin Peng, Douglas R. Green, Stephen White, R. Kiplin Guy, Taosheng Chen, Andrew M. Davidoff

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

43 Scopus citations

Abstract

Histone lysine demethylases facilitate the activity of oncogenic transcription factors, including possibly MYC. Here we show that multiple histone demethylases influence the viability and poor prognosis of neuroblastoma cells, where MYC is often overexpressed. We also identified the approved small-molecule antifungal agent ciclopirox as a novel pan-histone demethylase inhibitor. Ciclopirox targeted several histone demethylases, including KDM4B implicated in MYC function. Accordingly, ciclopirox inhibited Myc signaling in parallel with mitochondrial oxidative phosphorylation, resulting in suppression of neuroblastoma cell viability and inhibition of tumor growth associated with an induction of differentiation. Our findings provide new insights into epigenetic regulation of MYC function and suggest a novel pharmacologic basis to target histone demethylases as an indirect MYC-targeting approach for cancer therapy.

Original language	English
Pages (from-to)	4626-4638
Number of pages	13
Journal	Cancer Research
Volume	77
Issue number	17
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-0826
State	Published - Sep 1 2017

Bibliographical note

Publisher Copyright:
©2017 AACR.

Funding

This work was supported by the Assisi Foundation of Memphis, the US Public Health Service Childhood Solid Tumor Program Project Grant no. CA23099, the Cancer Center Support Grant no. 21766 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities (ALSAC) to A.M. Davidoff.

Funders	Funder number
US Public Health Service Childhood Solid Tumor Program	21766
National Childhood Cancer Registry – National Cancer Institute	P01CA023099
National Childhood Cancer Registry – National Cancer Institute
Assisi Foundation of Memphis
American Lebanese Syrian Associated Charities

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-16-0826

Cite this

Yang, J., Milasta, S., Hu, D., AlTahan, A. M., Interiano, R. B., Zhou, J., Davidson, J., Low, J., Lin, W., Bao, J., Goh, P., Nathwani, A. C., Wang, R., Wang, Y., Ong, S. S., Boyd, V. A., Young, B., Das, S., Shelat, A., ... Davidoff, A. M. (2017). Targeting histone demethylases in MYC-driven neuroblastomas with ciclopirox. Cancer Research, 77(17), 4626-4638. https://doi.org/10.1158/0008-5472.CAN-16-0826

@article{108b6ca36fc34e8a91170a46919c06da,

title = "Targeting histone demethylases in MYC-driven neuroblastomas with ciclopirox",

abstract = "Histone lysine demethylases facilitate the activity of oncogenic transcription factors, including possibly MYC. Here we show that multiple histone demethylases influence the viability and poor prognosis of neuroblastoma cells, where MYC is often overexpressed. We also identified the approved small-molecule antifungal agent ciclopirox as a novel pan-histone demethylase inhibitor. Ciclopirox targeted several histone demethylases, including KDM4B implicated in MYC function. Accordingly, ciclopirox inhibited Myc signaling in parallel with mitochondrial oxidative phosphorylation, resulting in suppression of neuroblastoma cell viability and inhibition of tumor growth associated with an induction of differentiation. Our findings provide new insights into epigenetic regulation of MYC function and suggest a novel pharmacologic basis to target histone demethylases as an indirect MYC-targeting approach for cancer therapy.",

author = "Jun Yang and Sandra Milasta and Dongli Hu and AlTahan, \{Alaa M.\} and Interiano, \{Rodrigo B.\} and Junfang Zhou and Jesse Davidson and Jonathan Low and Wenwei Lin and Ju Bao and Pollyanna Goh and Nathwani, \{Amit C.\} and Ruoning Wang and Yingdi Wang and Ong, \{Su Sien\} and Boyd, \{Vincent A.\} and Brandon Young and Sourav Das and Anang Shelat and Yinan Wu and Zhenmei Li and Zheng, \{Jie J.\} and Ashutosh Mishra and Yong Cheng and Chunxu Qu and Junmin Peng and Green, \{Douglas R.\} and Stephen White and Guy, \{R. Kiplin\} and Taosheng Chen and Davidoff, \{Andrew M.\}",

note = "Publisher Copyright: {\textcopyright}2017 AACR.",

year = "2017",

month = sep,

day = "1",

doi = "10.1158/0008-5472.CAN-16-0826",

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Yang, J, Milasta, S, Hu, D, AlTahan, AM, Interiano, RB, Zhou, J, Davidson, J, Low, J, Lin, W, Bao, J, Goh, P, Nathwani, AC, Wang, R, Wang, Y, Ong, SS, Boyd, VA, Young, B, Das, S, Shelat, A, Wu, Y, Li, Z, Zheng, JJ, Mishra, A, Cheng, Y, Qu, C, Peng, J, Green, DR, White, S, Guy, RK, Chen, T & Davidoff, AM 2017, 'Targeting histone demethylases in MYC-driven neuroblastomas with ciclopirox', Cancer Research, vol. 77, no. 17, pp. 4626-4638. https://doi.org/10.1158/0008-5472.CAN-16-0826

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AU - Yang, Jun

AU - Milasta, Sandra

AU - Hu, Dongli

AU - AlTahan, Alaa M.

AU - Interiano, Rodrigo B.

AU - Zhou, Junfang

AU - Davidson, Jesse

AU - Low, Jonathan

AU - Lin, Wenwei

AU - Bao, Ju

AU - Goh, Pollyanna

AU - Nathwani, Amit C.

AU - Wang, Ruoning

AU - Wang, Yingdi

AU - Ong, Su Sien

AU - Boyd, Vincent A.

AU - Young, Brandon

AU - Das, Sourav

AU - Shelat, Anang

AU - Wu, Yinan

AU - Li, Zhenmei

AU - Zheng, Jie J.

AU - Mishra, Ashutosh

AU - Cheng, Yong

AU - Qu, Chunxu

AU - Peng, Junmin

AU - Green, Douglas R.

AU - White, Stephen

AU - Guy, R. Kiplin

AU - Chen, Taosheng

AU - Davidoff, Andrew M.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Histone lysine demethylases facilitate the activity of oncogenic transcription factors, including possibly MYC. Here we show that multiple histone demethylases influence the viability and poor prognosis of neuroblastoma cells, where MYC is often overexpressed. We also identified the approved small-molecule antifungal agent ciclopirox as a novel pan-histone demethylase inhibitor. Ciclopirox targeted several histone demethylases, including KDM4B implicated in MYC function. Accordingly, ciclopirox inhibited Myc signaling in parallel with mitochondrial oxidative phosphorylation, resulting in suppression of neuroblastoma cell viability and inhibition of tumor growth associated with an induction of differentiation. Our findings provide new insights into epigenetic regulation of MYC function and suggest a novel pharmacologic basis to target histone demethylases as an indirect MYC-targeting approach for cancer therapy.

AB - Histone lysine demethylases facilitate the activity of oncogenic transcription factors, including possibly MYC. Here we show that multiple histone demethylases influence the viability and poor prognosis of neuroblastoma cells, where MYC is often overexpressed. We also identified the approved small-molecule antifungal agent ciclopirox as a novel pan-histone demethylase inhibitor. Ciclopirox targeted several histone demethylases, including KDM4B implicated in MYC function. Accordingly, ciclopirox inhibited Myc signaling in parallel with mitochondrial oxidative phosphorylation, resulting in suppression of neuroblastoma cell viability and inhibition of tumor growth associated with an induction of differentiation. Our findings provide new insights into epigenetic regulation of MYC function and suggest a novel pharmacologic basis to target histone demethylases as an indirect MYC-targeting approach for cancer therapy.

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SN - 0008-5472

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Targeting histone demethylases in MYC-driven neuroblastomas with ciclopirox

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

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