Journal
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
Volume 107, Issue 6, Pages -Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djv080
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Funding
- Assisi Foundation of Memphis
- US Public Health Service Childhood Solid Tumor Program [CA23099]
- Cancer Center Support Grant from the National Cancer Institute [21766]
- American Lebanese Syrian Associated Charities (ALSAC)
- Cancer Research UK [11359, 16466] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10163, NF-SI-0513-10071, RP-PG-0310-1001] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [26893309] Funding Source: KAKEN
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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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