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- Title
The Role of Histone Demethylase KDM4B in Myc Signaling in Neuroblastoma.
- Authors
Jun Yang; AlTahan, Alaa M.; Dongli Hu; Yingdi Wang; Pei-Hsin Cheng; Morton, Christopher L.; Chunxu Qu; Nathwani, Amit C.; Shohet, Jason M.; Fotsis, Theodore; Koster, Jan; Versteeg, Rogier; Hitoshi Okada; Harris, Adrian L.; Davidoff, Andrew M.
- 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-ofconcept for inhibition of histone demethylases to target Myc signaling in cancers such as neuroblastoma.
- Subjects
HISTONE demethylases; NEUROBLASTOMA; HISTONE methylation; NEOPLASTIC cell transformation; RANK correlation (Statistics); RNA interference; IMMUNOPRECIPITATION; IMMUNOFLUORESCENCE
- Publication
JNCI: Journal of the National Cancer Institute, 2015, Vol 107, Issue 6, p1
- ISSN
0027-8874
- Publication type
Article
- DOI
10.1093/jnci/djv080