The Role of Histone Demethylase KDM4B in Myc Signaling in Neuroblastoma

Yang, Jun; Altahan, Alaa; 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.

doi:10.1093/jnci/djv080

Cited by 69 publications

(76 citation statements)

References 46 publications

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“…The reproducibility of replicates was assessed by Pearson correlation and permutation tests (Figure S1A-D and Supplemental Experimental Procedures). Four of the top candidates in the screen, CENPE (Balamuth et al, 2010), BRD4 (Puissant et al, 2013), CHAF1A (Barbieri et al, 2014) and KDM4B (Yang et al, 2015) were already characterized as required for NB cell survival. We performed a validation screen using individual siRNAs against select candidate genes in SY5Y and BE2C (Figure 1C, for selection and validation criteria, see Supplemental Experimental Procedures).…”

Section: Resultsmentioning

confidence: 99%

Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma

et al. 2017

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Summary Given the paucity of druggable mutations in high-risk neuroblastoma (NB), we undertook chromatin-focused siRNA and chemical screens to uncover epigenetic regulators critical for the differentiation block in high-risk NB. High-content Opera imaging identified 53 genes whose loss of expression led to a decrease in NB cell proliferation and 16 also induced differentiation. From these, the secondary chemical screen identified SETD8, the H4K20me1 methyltransferase, as a druggable NB target. Functional studies revealed that SETD8 ablation rescued the proapoptotic and cell-cycle arrest functions of p53 by decreasing p53K382me1, leading to activation of the p53 canonical pathway. In pre-clinical xenograft NB models, genetic or pharmacological (UNC0379) SETD8 inhibition conferred a significant survival advantage, providing evidence for SETD8 as a therapeutic target in NB.

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Section: Resultsmentioning

confidence: 99%

Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma

et al. 2017

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“…See oligo sequences in the Supplemental section. For shRNA knockdown of KDM4B we used sh814 which had the best knockdown efficiency(14). …”

Section: Methodsmentioning

confidence: 99%

“…We have recently shown that KDM4B interacts with N-Myc to maintain low levels of the repressive transcription mark, H3K9me3/me2, in neuroblastoma, resulting in overexpression of genes that promote tumor progression (14). Therefore, targeting histone demethylases may block the activities of oncogenic transcription factors and activate tumor suppressive pathways, thereby achieving therapeutic efficacy.…”

Section: Introductionmentioning

confidence: 99%

Targeting Histone Demethylases in MYC-Driven Neuroblastomas with Ciclopirox

Yang

Milasta

et al. 2017

Cancer Research

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Histone lysine demethylases facilitate the activity of oncogenic transcription factors including possibly MYC. Here we show that multiple histone demethylases influence the viability and poor prognosis of neuroblastoma cells where MYC is often overexpressed. We also identified the approved small molecule antifungal agent ciclopirox as a novel pan-histone demethylase inhibitor. Ciclopirox targeted several histone demethylases including KDM4B implicated in MYC function. Accordingly, ciclopirox inhibited Myc signaling in parallel with mitochondrial oxidative phosphorylation, resulting in suppression of neuroblastoma cell viability and inhibition of tumor growth associated with an induction of differentiation. Our findings provide new insights into epigenetic regulation of MYC function and suggest a novel pharmacologic basis to target histone demethylases as an indirect MYC targeting approach for cancer therapy.

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“…It specifically demethylates lysine 9 of histone H3 (H3K9me3/me2), removing repressive chromatin marks, thereby contributing to gene activation [45]. This mechanism was reported for MYC in embryonic stem cells (ESCs) and for overexpressed N-MYC in neuroblastoma [43,44], indicating that the decreased H3K9me3 deposition plays a role for both MYC’s physiologic as well as its oncogenic function. While the elevated expression of KDM4B in N-MYC amplified neuroblastomas is associated with poor clinical outcome, inhibition of KDM4B suppresses MYC function.…”

Section: Recruitment Of Chromatin Modifiers For Myc-dependent Tranmentioning

confidence: 99%

MYC—Master Regulator of the Cancer Epigenome and Transcriptome

Poole

Riggelen

2017

Genes

133

114

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Overexpression of MYC is a hallmark of many human cancers. The MYC oncogene has long been thought to execute its neoplastic functions by acting as a classic transcription factor, deregulating the expression of a large number of specific target genes. However, MYC’s influence on many of these target genes is rather modest and there is little overlap between MYC regulated genes in different cell types, leaving many mechanistic questions unanswered. Recent advances in the field challenge the dogma further, revealing a role for MYC that extends beyond the traditional concept of a sequence-specific transcription factor. In this article, we review MYC’s function as a regulator of the cancer epigenome and transcriptome. We outline our current understanding of how MYC regulates chromatin structure in both a site-specific and genome-wide fashion, and highlight the implications for therapeutic strategies for cancers with high MYC expression.

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The Role of Histone Demethylase KDM4B in Myc Signaling in Neuroblastoma

Abstract: 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.

Cited by 69 publications

References 46 publications

Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma

Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma

Targeting Histone Demethylases in MYC-Driven Neuroblastomas with Ciclopirox

MYC—Master Regulator of the Cancer Epigenome and Transcriptome

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