Abstract
MYCN gene amplification in neuroblastoma drives a gene expression program that correlates strongly with aggressive disease. Mechanistically, trimethylation of histone H3 lysine 4 (H3K4) at target gene promoters is a strict prerequisite for this transcriptional program to be enacted. WDR5 is a histone H3K4 presenter that has been found to have an essential role in H3K4 trimethylation. For this reason, in this study, we investigated the relationship between WDR5-mediated H3K4 trimethylation and N-Myc transcriptional programs in neuroblastoma cells. N-Myc upregulated WDR5 expression in neuroblastoma cells. Gene expression analysis revealed that WDR5 target genes included those with MYC-binding elements at promoters such as MDM2. We showed that WDR5 could form a protein complex at the MDM2 promoter with N-Myc, but not p53, leading to histone H3K4 trimethylation and activation of MDM2 transcription. RNAi-mediated attenuation of WDR5 upregulated expression of wild-type but not mutant p53, an effect associated with growth inhibition and apoptosis. Similarly, a small-molecule antagonist of WDR5 reduced N-Myc/WDR5 complex formation, N-Myc target gene expression, and cell growth in neuroblastoma cells. In MYCN-transgenic mice, WDR5 was overexpressed in precancerous ganglion and neuroblastoma cells compared with normal ganglion cells. Clinically, elevated levels of WDR5 in neuroblastoma specimens were an independent predictor of poor overall survival. Overall, our results identify WDR5 as a key cofactor for N-Myc-regulated transcriptional activation and tumorigenesis and as a novel therapeutic target for MYCN-amplified neuroblastomas.
Highlights
Neuroblastoma is the most common solid tumor in early childhood [1, 2]
By analyzing 35 histone marks after genomic binding by Myc, Guccione and colleagues have revealed that histone H3 lysine 4 (H3K4) trimethylation at Myc-responsive elements of target gene promoters is a strict prerequisite for Myc-induced transcriptional activation [11]
We showed, for the first time, that WDR5 formed a protein complex with N-Myc at N-Myc target gene promoters, leading to histone H3K4 trimethylation, transcriptional activation of the N-Myc target genes, including MDM2, and reduction in wild-type p53 protein, that repression of WDR5 resulted in neuroblastoma cell growth inhibition and apoptosis, and that high levels of WDR5 expression in human neuroblastoma tissues independently predicted poor patient prognosis
Summary
Neuroblastoma is the most common solid tumor in early childhood [1, 2]. It accounts for approximately 15% of all childhood cancer-related death despite the use of combination chemotherapy, radiotherapy, and bone marrow transplantation [1, 3]. By direct binding to Oct and causing H3K4 trimethylation at Oct target gene promoters, WDR5 activates the transcription of Oct target genes and is required for the formation of induced pluripotent stem cells [16]. By direct binding to MLL and causing histone H3K4 trimethylation at MLL target gene promoters, WDR5 induces the transcription of MLL target genes and promotes leukemia [13,14,15]. We showed, for the first time, that WDR5 formed a protein complex with N-Myc at N-Myc target gene promoters, leading to histone H3K4 trimethylation, transcriptional activation of the N-Myc target genes, including MDM2, and reduction in wild-type p53 protein, that repression of WDR5 resulted in neuroblastoma cell growth inhibition and apoptosis, and that high levels of WDR5 expression in human neuroblastoma tissues independently predicted poor patient prognosis
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