The Histone Methyltransferase DOT1L Promotes Neuroblastoma by Regulating Gene Transcription

Abstract

Myc oncoproteins exert tumorigenic effects by regulating 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, and DOT1L is the only known histone methyltransferase that catalyzes H3K79 methylation. Here, we show that N-Myc upregulates DOT1L mRNA and protein expression by binding to the DOT1L gene promoter. shRNA-mediated depletion of DOT1L reduced mRNA and protein expression of N-Myc target genes and DOT1L bound to the Myc Box II domain of N-Myc protein, and knockdown of 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 gene-amplified neuroblastoma cells. In mice xenografts of neuroblastoma cells stably expressing doxycycline-inducible DOT1L shRNA, 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, and gene expression and independently correlated with poor patient survival. Taken together, our results identify DOT1L as a novel cofactor in N-Myc-mediated transcriptional activation of target genes and neuroblastoma oncogenesis. Furthermore, they characterize DOT1L inhibitors as novel anticancer agents against MYCN-amplified neuroblastoma..

Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma

“…To this point, Veschi et al . (8) recently reported that the lysine methyltransferase Su(var)3-9 enhancer-of-zeste and trithorax domain containing 8 (SETD8) is a promising therapeutic target in high-risk neuroblastomas, and disruptor of telomeric silencing-1–like histone lysine methyltransferase (DOT1L) was recently reported to act as a key cofactor in MYCN-induced transcripts in neuroblastoma (48). …”

Epigenetic priming by Dot1l in lymphatic endothelial progenitors ensures normal lymphatic development and function

“…Accumulating evidence suggests that DOT1L has contextdependent beneficial or adverse effects on human disease. For example, DOT1L promotes the progression of neuroblastoma, whereas it protects against the development of UV-induced melanoma 48,49 . Nguyen et al demonstrated that Dot1l function is essential for the normal maintenance of cardiovascular homeostasis, as a loss of Dot1l function in cardiomyocytes led to dilated cardiomyopathy, with repressed dystrophin expression 31 .…”

The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+T cells

“…The histone methyltransferase DOT1L has emerged as a druggable target in MLL-rearranged leukemia and additional roles in cancer have been suggested [22][23][24][65][66][67][68] . This in combination with the availability of highly-specific DOT1L inhibitors make DOT1L a potential target for cancer therapy.…”