Poster Presentation Advances in Neuroblastoma Research Congress 2016

The histone H3 lysine 4 presenter WDR5 is a potential therapeutic target in N-Myc-induced neuroblastoma. (#260)

Yuting Sun 1 , Jessica Bell 2 , Daniel Carter 1 , Samuele Gherardi 3 , Rebecca Poulos 4 , Giorgio Milazzo 3 , Jason Wong 4 , Rima Al-Awar 5 , Andrew Tee 1 , Bing Liu 1 , Pei Yan Liu 1 , Bernard Atmadibrata 1 , Matthew Wong 1 , Toby Trahair 1 , Ygal Haupt 6 , Peter Brown 7 , Cheryl Arrowsmith 7 , Masoud Vedadi 7 , Karen MacKenzie 1 , Stefan Hüttelmaier 2 , Giovanni Perini 3 , Glenn Marshall 1 , Antony Braithwaite 8 , Tao Liu 1
  1. Children's Cancer Institute Australia, Randwick, NSW, Australia
  2. Institute of Molecular Medicine, Martin Luther University, ZAMED, Halle, Germany
  3. Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
  4. Prince of Wales Clinical School and Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, NSW, Australia
  5. Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada
  6. Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, East Melbourne,, Victoria, Australia
  7. Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada
  8. Department of Pathology , University of Otago, Otago, Dunedin , New Zealand

Neuroblastoma is a cancer of the sympathetic nervous system occurring mostly in infants and young children. It accounts for more than 10% of all paediatric cancer deaths. Despite considerable progress in the treatment of neuroblastoma, 5-year survival rates have remained less than 50% for the majority of children with high-risk disease. One of the most powerful prognostic markers for this disease is amplification of the MYCN oncogene, which has been found in approximately one third of neuroblastomas and nearly half of high-risk cases. Although MYCN has a clearly central role in neuroblastoma tumorigenesis, the critical molecular mechanisms of high-risk neuroblastoma have not yet been well understood for clinical use. Histone H3 lysine 4 (H3K4) trimethylation at target gene promoters is a strict pre-requisite for Myc-induced transcriptional activation. We have identified WD-repeat protein 5 (WDR5), a core component of many H3K4 methyltransferase complexes, interacts with N-Myc, leading to WDR5-mediated H3K4 trimethylation and N-Myc-regulated transcriptional activation in neuroblastoma cells. Furthermore, we have demonstrated RNAi-mediated attenuation of WDR5 upregulated expression of wild type but not mutant p53, an effect associated with growth inhibition and apoptosis in neuroblastoma. In addition, WDR5 was over-expressed in pre-cancer ganglia and neuroblastoma cells from MYCN transgenic mice, compared with normal ganglia cells. In neuroblastoma patients, high levels of WDR5 expression in tumor tissues independently predicted poor overall survival. Importantly, we have identified that OICR-9429 exerts a dose-responsive, inhibitory effect in MYCN-amplified neuroblastoma cells viability. Moreover, we have founded that OICR-9429 modulates the expression of N-Myc target genes CCNE1, MDM2 and p53. Of note, we have showed that OICR-9429 blocks WDR5-N-Myc protein interaction. Our findings therefore identify WDR5 as an important biomarker for N-Myc-regulated transcriptional activation and tumorigenesis, and as a novel therapeutic target for N-Myc over-expressing neuroblastoma.