+441518081136Histone modification enzymes are critical for N-Myc-driven gene transcription and tumourigenesis
International Conference on Oncology and Cancer Therapeutics
October 30- November 01, 2017 | Chicago, USA
Tao Liu
The University of New South Wales, Australia
Scientific Tracks Abstracts : J Med Oncl Ther
Abstract:
Myc oncoproteins exert tumorigenic effects by regulating the expression of target oncogenes. We previously show that the histone H3 lysine four presenters WDR5 promotes N-Myc-mediated gene transcription and tumour cell proliferation. Histone H3 lysine79 (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 catalyses 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 bound to the Myc Box II domain of N-Myc protein, 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. Treatment with the small molecule DOT1L inhibitor SGC0946 reduced H3K79 methylation and proliferation of MYCN gene-amplified neuroblastoma cells. In mice xenografted with neuroblastoma cells stably expressing doxycycline-inducible DOT1L small hair-pin RNA, ablating DOT1L expression with doxycycline significantly reduced ODC1 and E2F2 expression, reduced tumor progression and improved overall survival. 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 DOT1L inhibitors as novel anticancer agents against MYCN-amplified neuroblastoma.
Biography:
Tao Liu is originally trained as a Medical Practitioner specializing in Neurology and an Associate Professor. He studied for a PhD degree at The University of New South Wales, Sydney, Australia on the role of inflammatory mediators in chronic pain due to nerve injury. He then worked on the role of MIC-1, a new member of the transforming growth factor beta superfamily, in cancer cell proliferation, survival/apoptosis and metastasis at St. Vincent’s Centre for Applied Medical Research, Sydney, Australia. He is an Associate Professor and joined Children’s Cancer Institute Australia for Medical Research ten years ago. He has been focusing his research on the roles of histone deacetylases, histone demethylases, and histone methyltransferases, BET bromodomains proteins and long noncoding RNAs in modulating gene transcription and tumourigenesis, and the roles of histone deacetylase inhibitors, histone methyltransferase inhibitors and BET bromodomain inhibitors as anticancer agents in vitro and in mouse models of cancer.
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