The role of histone demethylase KDM4B in Myc signaling in neuroblastoma.

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.

• Authors: 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
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 107 Issue 6 Pg. djv080 (Jun 2015) ISSN: 1460-2105 [Electronic] United States
• PMID: 25925418 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• MYC protein, human
• Proto-Oncogene Proteins c-myc
• Jumonji Domain-Containing Histone Demethylases
• KDM4B protein, human

Topics

• Animals
• Cell Differentiation
• Cell Line, Tumor
• Cell Proliferation
• Chromatin Immunoprecipitation
• DNA Methylation
• Gene Expression Regulation, Neoplastic
• Heterografts
• Humans
• Jumonji Domain-Containing Histone Demethylases (metabolism)
• Kaplan-Meier Estimate
• Mice
• Neuroblastoma (genetics, metabolism)
• Prognosis
• Protein Array Analysis
• Proto-Oncogene Proteins c-myc (metabolism)
• Real-Time Polymerase Chain Reaction