Oral Presentation Advances in Neuroblastoma Research Congress 2016

The histone methyltransferase DOT1L induces neuroblastoma progression by regulating gene transcription (#83)

Andrew E Tee 1 2 , Matthew Wong 1 , Jessica Bell 3 , Yuting Sun 1 , Pei Yan Liu 1 , Stefan Hüttelmaier 3 , Patsie Polly 4 , Chris J Scarlett 5 , Tao Liu 1 6
  1. Children's Cancer Institute, Sydney, NSW, Australia
  2. School of Women's & Children's Health, UNSW Medicine,, University of New South Wales, Randwick, NSW, Australia
  3. Institute of Molecular Medicine, Martin Luther University, ZAMED, 06120 Halle, Germany
  4. Department of Pathology and Inflammation and Infection Research Centre, University of New South Wales, Kensington, NSW 2052, Australia
  5. School of Environmental & Life Sciences, University of Newcastle, Ourimbah, NSW, Australia
  6. Centre for Childhood Cancer Research, UNSW Medicine, UNSW Australia, Kensington, Sydney, NSW 2052, Australia

Myc oncoproteins exert oncogenic effects by regulating the expression of target oncogenes. Histone H3 lysine 79 (H3K79) methylation at Myc-responsive elements of target gene promoters is a strict prerequisites for Myc-induced transcriptional activation. DOT1L is the only known histone methyltransferase that catalyses H3K79 methylation. Here, we showed that N-Myc up-regulated DOT1L mRNA and protein expression by binding to an E-box at the DOT1L gene promoter. Knocking-down DOT1L reduced the mRNA and protein expression of the N-Myc target genes, ODC1 and E2F2. DOT1L and N-Myc formed a protein complex, and knocking-down DOT1L reduced histone H3K79 di-methylation and N-Myc protein binding at the ODC1 and E2F2 promoters, reduced neuroblastoma cell proliferation in vitro and tumour progression in neuroblastoma-bearing mice. In addition, high levels of DOT1L gene expression in neuroblastoma tissues correlated with high levels of MYCN, ODC1 and E2F2 gene expression, and independently correlated with poor patient survival. Taken together, our data identify DOT1L as a novel co-factor in N-Myc-mediated gene transcriptional activation and neuroblastoma oncogenesis, and as a novel target for the therapy of neuroblastoma.