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- Title
The role of histone demethylase KDM4B in Myc signaling in neuroblastoma.
- Authors
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
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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).<bold>Conclusions: </bold>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.
- Publication
JNCI: Journal of the National Cancer Institute, 2015, Vol 107, Issue 6, p1
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djv080