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J Med Oncl Ther 2017 Volume 2 | Issue 3
International Conference on
Oncology and Cancer Therapeutics
October 30- November 01, 2017 | Chicago, USA
Histone modification enzymes are critical for N-Myc-driven gene transcription and tumourigenesis
Tao Liu
The University of New South Wales, Australia
M
yc 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.
Speaker 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 newmember of the transforming growth
factor beta superfamily, in cancer cell proliferation, survival/apoptosis andmetastasis 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.
e:
tliu@unsw.edu.au