The Roles of Histone Deacetylase 5 and the Histone Methyltransferase Adaptor WDR5 in Myc oncogenesis.

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Embargoed until 2016-11-30
Copyright: Sun, Yuting
N-Myc induces neuroblastoma by regulating the expression of target genes and proteins, and N-Myc protein is degraded by Fbxw7 and NEDD4 and stabilized by Aurora A. The class IIa histone deacetylase HDAC5 suppresses gene transcription, and blocks myoblast and leukaemia cell differentiation. While histone H3 lysine 4 (H3K4) trimethylation at target gene promoters is a pre-requisite for Myc-induced transcriptional activation, WDR5, as a histone H3K4 methyltransferase presenter, is required for H3K4 methylation and transcriptional activation mediated by a histone H3K4 methyltransferase complex. Here, I investigated the roles of HDAC5 and WDR5 in N-Myc overexpressing neuroblastoma. I have found that N-Myc upregulates HDAC5 protein expression, and that HDAC5 represses NEDD4 gene expression, increases Aurora A gene expression and consequently upregulates N-Myc protein expression in neuroblastoma cells. HDAC5 and N-Myc commonly repress the expression of a subset of genes by forming a protein complex, while HDAC5 and the class III HDAC SIRT2 commonly, but independently, repress the expression of another subset of genes. Moreover, HDAC5 blocks cell differentiation and induces cell proliferation. I have also demonstrated that N-Myc upregulates WDR5 gene expression by binding to the WDR5 gene promoter. Conversely, WDR5 forms a protein complex with N-Myc at the gene promoter of N-Myc target genes, leading to histone H3K4 trimethylation and transcriptional activation of N-Myc target genes, including MDM2 and CCNE1. Importantly, WDR5 reduces the expression of wild type, but not mutant, p53 protein expression in MYCN oncogene-amplified neuroblastoma cells through reducing MDM2 expression, induces neuroblastoma cell proliferation in p53 dependent/independent fashions, and enhances neuroblastoma cell survival in a p53-dependent manner. In a publicly available large cohort of 476 neuroblastoma patients, high levels of WDR5 gene expression in tumours correlate with poor patient survival independent of MYCN amplification and disease stage. In addition, treatment with WDR5 inhibitors blocks the formation of N-Myc and WDR5 protein complex, reduces the expression of N-Myc and WDR5 target genes, and impedes neuroblastoma cell proliferation. In conclusion, these data identify HDAC5 and WDR5 as novel co-factors in N-Myc oncogenesis, and provide the critical evidence for the potential utilization of WDR5 inhibitors for the therapy of neuroblastoma.
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Sun, Yuting
Liu, Tao
Mackenzie, Karen
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PhD Doctorate
UNSW Faculty
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