The critical role of histone methylation in tumour progression and as anti-cancer targets in neuroblastoma

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Embargoed until 2017-04-30
Copyright: Wong, Matthew
N-Myc induces neuroblastoma 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 mono-methylation (me), di-methylation (me2) and tri-methylation (me3) at the histone H3K79 position, which have been linked to gene transcriptional activation. JMJD6 is a bi-functional arginine demethylase and lysyl-hydroxylase. The JMJD6 gene is located on the chromosome 17q25 position. 17q21-gter gain has been identified as the most frequent chromosome alternation in neuroblastoma and an indicator of poor patient prognostic. Here, I investigated the roles of DOT1L and JMJD6 in N-Myc over-expressing neuroblastoma. I found 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 H3K79me2 and N-Myc protein binding at the promoters of the N-Myc target genes ODC1 and E2F2, and reduced neuroblastoma cell proliferation in vitro and tumour progression in neuroblastoma-bearing mice. In a publicly available microarray gene expression dataset, high levels of DOT1L gene expression in tumours correlated with high levels of MYCN gene expression and poor patient survival independent of MYCN amplification, age at diagnosis and disease stage. I have also demonstrated that JMJD6 up-regulated both N-Myc and c-Myc in neuroblastoma cell lines. Conversely N-Myc and c-Myc did not affect JMJD6 mRNA or protein expression. Knocking down JMJD6 reduced neuroblastoma cell proliferation in vitro and tumour progression in neuroblastoma-bearing mice. JMJD6 gene expression correlated with MYCN gene expression in human neuroblastoma tissue microarray gene expression datasets. High DOT1L gene expression was also a prognostic factor for poor neuroblastoma patient outcome. In conclusion, these data identify DOT1L as a novel co-factor in N-Myc oncogenesis, and provide critical evidence for the potential utilization of DOT1L inhibitors for the therapy of MYCN amplified neuroblastoma. JMJD6 up-regulates N-Myc and c-Myc gene expression and JMJD6 gene gain is a potential mechanism for 17q21-qter gain driven neuroblastoma tumourigenesis.
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Wong, Matthew
Liu, Tao
Polly, Patsie
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PhD Doctorate
UNSW Faculty
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