The role of histone demethylase KDM4B in Myc signaling in neuroblastoma

Jun Yang, Alaa M. Altahan, Dongli Hu, Yingdi Wang, Pei Hsin Cheng, Christopher L. Morton, Chunxu Qu, Amit C. Nathwani, Jason M. Shohet, Theodore Fotsis, Jan Koster, Rogier Versteeg, Hitoshi Okada, Adrian L. Harris, Andrew M. Davidoff

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Abstract

Background: Epigenetic alterations, such as histone methylation, modulate Myc signaling, a pathway central to oncogenesis. We investigated the role of the histone demethylase KDM4B in N-Myc-mediated neuroblastoma pathogenesis. Methods: Spearman correlation was performed to correlate MYCN and KDM4B expression. RNA interference, microarray analysis, gene set enrichment analysis, and real-time polymerase chain reaction were used to define the functions of KDM4B. Immunoprecipitation and immunofluorescence were used to assess protein-protein interactions between N-Myc and KDM4B. Chromatin immunoprecipitation was used to assess the binding of Myc targets. Constitutive and inducible lentiviral-mediated KDM4B knockdown with shRNA was used to assess the effects on tumor growth. Kaplan-Meier survival analysis was used to assess the prognostic value of KDM4B expression. All statistical tests were two-sided. Results: KDM4B and MYCN expression were found to be statistically significantly correlated in a variety of cancers, including neuroblastoma (R = 0.396, P <. 001). Functional studies demonstrated that KDM4B regulates the Myc pathway. N-Myc was found to physically interact with and recruit KDM4B. KDM4B was found to regulate neuroblastoma cell proliferation and differentiation in vitro and xenograft growth in vivo (5 mice/group, two-tailed t test, P ≤ 0.001). Finally, together with MYCN amplification, KDM4B was found to stratify a subgroup of poor-prognosis patients (122 case patients, P <. 001). Conclusions: Our findings provide insight into the epigenetic regulation of Myc via histone demethylation and proof-of-concept for inhibition of histone demethylases to target Myc signaling in cancers such as neuroblastoma.

Original languageEnglish (US)
Article numberdjv080
JournalJournal of the National Cancer Institute
Volume107
Issue number6
DOIs
StatePublished - Jun 1 2015

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Histone Demethylases
Neuroblastoma
Epigenomics
Histones
Neoplasms
Chromatin Immunoprecipitation
Kaplan-Meier Estimate
Microarray Analysis
Survival Analysis
Growth
RNA Interference
Immunoprecipitation
Heterografts
Methylation
Small Interfering RNA
Fluorescent Antibody Technique
Real-Time Polymerase Chain Reaction
Cell Differentiation
Carcinogenesis
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Yang, J., Altahan, A. M., Hu, D., Wang, Y., Cheng, P. H., Morton, C. L., ... Davidoff, A. M. (2015). The role of histone demethylase KDM4B in Myc signaling in neuroblastoma. Journal of the National Cancer Institute, 107(6), [djv080]. https://doi.org/10.1093/jnci/djv080

The role of histone demethylase KDM4B in Myc signaling in neuroblastoma. / Yang, Jun; Altahan, Alaa M.; Hu, Dongli; Wang, Yingdi; Cheng, Pei Hsin; Morton, Christopher L.; Qu, Chunxu; Nathwani, Amit C.; Shohet, Jason M.; Fotsis, Theodore; Koster, Jan; Versteeg, Rogier; Okada, Hitoshi; Harris, Adrian L.; Davidoff, Andrew M.

In: Journal of the National Cancer Institute, Vol. 107, No. 6, djv080, 01.06.2015.

Research output: Contribution to journalArticle

Yang, J, Altahan, AM, Hu, D, Wang, Y, Cheng, PH, Morton, CL, Qu, C, Nathwani, AC, Shohet, JM, Fotsis, T, Koster, J, Versteeg, R, Okada, H, Harris, AL & Davidoff, AM 2015, 'The role of histone demethylase KDM4B in Myc signaling in neuroblastoma', Journal of the National Cancer Institute, vol. 107, no. 6, djv080. https://doi.org/10.1093/jnci/djv080
Yang, Jun ; Altahan, Alaa M. ; Hu, Dongli ; Wang, Yingdi ; Cheng, Pei Hsin ; Morton, Christopher L. ; Qu, Chunxu ; Nathwani, Amit C. ; Shohet, Jason M. ; Fotsis, Theodore ; Koster, Jan ; Versteeg, Rogier ; Okada, Hitoshi ; Harris, Adrian L. ; Davidoff, Andrew M. / The role of histone demethylase KDM4B in Myc signaling in neuroblastoma. In: Journal of the National Cancer Institute. 2015 ; Vol. 107, No. 6.
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abstract = "Background: Epigenetic alterations, such as histone methylation, modulate Myc signaling, a pathway central to oncogenesis. We investigated the role of the histone demethylase KDM4B in N-Myc-mediated neuroblastoma pathogenesis. Methods: Spearman correlation was performed to correlate MYCN and KDM4B expression. RNA interference, microarray analysis, gene set enrichment analysis, and real-time polymerase chain reaction were used to define the functions of KDM4B. Immunoprecipitation and immunofluorescence were used to assess protein-protein interactions between N-Myc and KDM4B. Chromatin immunoprecipitation was used to assess the binding of Myc targets. Constitutive and inducible lentiviral-mediated KDM4B knockdown with shRNA was used to assess the effects on tumor growth. Kaplan-Meier survival analysis was used to assess the prognostic value of KDM4B expression. All statistical tests were two-sided. Results: KDM4B and MYCN expression were found to be statistically significantly correlated in a variety of cancers, including neuroblastoma (R = 0.396, P <. 001). Functional studies demonstrated that KDM4B regulates the Myc pathway. N-Myc was found to physically interact with and recruit KDM4B. KDM4B was found to regulate neuroblastoma cell proliferation and differentiation in vitro and xenograft growth in vivo (5 mice/group, two-tailed t test, P ≤ 0.001). Finally, together with MYCN amplification, KDM4B was found to stratify a subgroup of poor-prognosis patients (122 case patients, P <. 001). Conclusions: Our findings provide insight into the epigenetic regulation of Myc via histone demethylation and proof-of-concept for inhibition of histone demethylases to target Myc signaling in cancers such as neuroblastoma.",
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AU - Yang, Jun

AU - Altahan, Alaa M.

AU - Hu, Dongli

AU - Wang, Yingdi

AU - Cheng, Pei Hsin

AU - Morton, Christopher L.

AU - Qu, Chunxu

AU - Nathwani, Amit C.

AU - Shohet, Jason M.

AU - Fotsis, Theodore

AU - Koster, Jan

AU - Versteeg, Rogier

AU - Okada, Hitoshi

AU - Harris, Adrian L.

AU - Davidoff, Andrew M.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - Background: Epigenetic alterations, such as histone methylation, modulate Myc signaling, a pathway central to oncogenesis. We investigated the role of the histone demethylase KDM4B in N-Myc-mediated neuroblastoma pathogenesis. Methods: Spearman correlation was performed to correlate MYCN and KDM4B expression. RNA interference, microarray analysis, gene set enrichment analysis, and real-time polymerase chain reaction were used to define the functions of KDM4B. Immunoprecipitation and immunofluorescence were used to assess protein-protein interactions between N-Myc and KDM4B. Chromatin immunoprecipitation was used to assess the binding of Myc targets. Constitutive and inducible lentiviral-mediated KDM4B knockdown with shRNA was used to assess the effects on tumor growth. Kaplan-Meier survival analysis was used to assess the prognostic value of KDM4B expression. All statistical tests were two-sided. Results: KDM4B and MYCN expression were found to be statistically significantly correlated in a variety of cancers, including neuroblastoma (R = 0.396, P <. 001). Functional studies demonstrated that KDM4B regulates the Myc pathway. N-Myc was found to physically interact with and recruit KDM4B. KDM4B was found to regulate neuroblastoma cell proliferation and differentiation in vitro and xenograft growth in vivo (5 mice/group, two-tailed t test, P ≤ 0.001). Finally, together with MYCN amplification, KDM4B was found to stratify a subgroup of poor-prognosis patients (122 case patients, P <. 001). Conclusions: Our findings provide insight into the epigenetic regulation of Myc via histone demethylation and proof-of-concept for inhibition of histone demethylases to target Myc signaling in cancers such as neuroblastoma.

AB - Background: Epigenetic alterations, such as histone methylation, modulate Myc signaling, a pathway central to oncogenesis. We investigated the role of the histone demethylase KDM4B in N-Myc-mediated neuroblastoma pathogenesis. Methods: Spearman correlation was performed to correlate MYCN and KDM4B expression. RNA interference, microarray analysis, gene set enrichment analysis, and real-time polymerase chain reaction were used to define the functions of KDM4B. Immunoprecipitation and immunofluorescence were used to assess protein-protein interactions between N-Myc and KDM4B. Chromatin immunoprecipitation was used to assess the binding of Myc targets. Constitutive and inducible lentiviral-mediated KDM4B knockdown with shRNA was used to assess the effects on tumor growth. Kaplan-Meier survival analysis was used to assess the prognostic value of KDM4B expression. All statistical tests were two-sided. Results: KDM4B and MYCN expression were found to be statistically significantly correlated in a variety of cancers, including neuroblastoma (R = 0.396, P <. 001). Functional studies demonstrated that KDM4B regulates the Myc pathway. N-Myc was found to physically interact with and recruit KDM4B. KDM4B was found to regulate neuroblastoma cell proliferation and differentiation in vitro and xenograft growth in vivo (5 mice/group, two-tailed t test, P ≤ 0.001). Finally, together with MYCN amplification, KDM4B was found to stratify a subgroup of poor-prognosis patients (122 case patients, P <. 001). Conclusions: Our findings provide insight into the epigenetic regulation of Myc via histone demethylation and proof-of-concept for inhibition of histone demethylases to target Myc signaling in cancers such as neuroblastoma.

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