Hereditary Genetics: Current Research

The histone H3K79 methyltransferase DOT1L regulates gene transcription and promotes neuroblastoma tumourigenesis

4^th International Congress on Epigenetics & Chromatin

September 03-05, 2018 | London, UK

Tao Liu

Histone Modification Group Children's Cancer Institute, Australia

Keynote: Hereditary Genet Curr Res

Abstract:

Myc oncoproteins exert tumorigenic 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 prerequisite for Myc-induced transcriptional activation. DOT1L is the only known histone methyltransferase that catalysis H3K79 methylation. Here, we showed that N-Myc up-regulated DOT1L mRNA and protein expression by binding to the DOT1L gene promoter. Knocking down DOT1L reduced 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 methylation and N-Myc protein binding at the ODC1 and E2F2 gene promoters and reduced neuroblastoma cell proliferation. Ablating DOT1L expression with doxycycline significantly reduced ODC1 and E2F2 expression, reduced tumor progression and improved overall survival in mice xenografted with neuroblastoma cells stably expressing doxycycline-inducible DOT1L small hair-pin RNA. In addition, high levels of DOT1L gene expression in human 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 transcriptional activation of target genes and neuroblastoma oncogenesis, and as a target for novel therapeutic strategies against neuroblastoma.

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