The Histone Methyltransferase DOT1L Promotes Neuroblastoma by Regulating Gene Transcription.

Wong, M; Tee, AEL; Milazzo, G; Bell, JL; Poulos, RC; Atmadibrata, B; Sun, Y; Jing, D; Ho, N; Ling, D; Liu, PY; Zhang, XD; Hüttelmaier, S; Wong, JWH; Wang, J; Polly, P; Perini, G; Scarlett, CJ; Liu, T

The Histone Methyltransferase DOT1L Promotes Neuroblastoma by Regulating Gene Transcription.

Wong, M Tee, AEL Milazzo, G Bell, JL Poulos, RC Atmadibrata, B Sun, Y Jing, D

Ho, N Ling, D Liu, PY Zhang, XD Hüttelmaier, S Wong, JWH Wang, J Polly, P Perini, G Scarlett, CJ Liu, T

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Publisher:: AMER ASSOC CANCER RESEARCH
Publication Type:: Journal Article
Citation:: Cancer Res, 2017, 77, (9), pp. 2522-2533
Issue Date:: 2017-05-01

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Field	Value	Language
dc.contributor.author	Wong, M
dc.contributor.author	Tee, AEL
dc.contributor.author	Milazzo, G
dc.contributor.author	Bell, JL
dc.contributor.author	Poulos, RC
dc.contributor.author	Atmadibrata, B
dc.contributor.author	Sun, Y
dc.contributor.author	Jing, D https://orcid.org/0000-0002-1491-8002
dc.contributor.author	Ho, N
dc.contributor.author	Ling, D
dc.contributor.author	Liu, PY
dc.contributor.author	Zhang, XD
dc.contributor.author	Hüttelmaier, S
dc.contributor.author	Wong, JWH
dc.contributor.author	Wang, J
dc.contributor.author	Polly, P
dc.contributor.author	Perini, G
dc.contributor.author	Scarlett, CJ
dc.contributor.author	Liu, T
dc.date.accessioned	2022-10-03T21:45:28Z
dc.date.available	2017-01-17
dc.date.available	2022-10-03T21:45:28Z
dc.date.issued	2017-05-01
dc.identifier.citation	Cancer Res, 2017, 77, (9), pp. 2522-2533
dc.identifier.issn	0008-5472
dc.identifier.issn	1538-7445
dc.identifier.uri	http://hdl.handle.net/10453/162260
dc.description.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 ODC1 and E2F2 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 MYCN 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 MYCN, ODC1, and E2F2 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. Cancer Res; 77(9); 2522-33. ©2017 AACR.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	AMER ASSOC CANCER RESEARCH
dc.relation.ispartof	Cancer Res
dc.relation.isbasedon	10.1158/0008-5472.CAN-16-1663
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	Animals
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	DNA Methylation
dc.subject.mesh	Enzyme Inhibitors
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Histone Methyltransferases
dc.subject.mesh	Histone-Lysine N-Methyltransferase
dc.subject.mesh	Humans
dc.subject.mesh	Methyltransferases
dc.subject.mesh	Mice
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Promoter Regions, Genetic
dc.subject.mesh	Transcription, Genetic
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Methyltransferases
dc.subject.mesh	Histone-Lysine N-Methyltransferase
dc.subject.mesh	Enzyme Inhibitors
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	DNA Methylation
dc.subject.mesh	Transcription, Genetic
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Promoter Regions, Genetic
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Histone Methyltransferases
dc.title	The Histone Methyltransferase DOT1L Promotes Neuroblastoma by Regulating Gene Transcription.
dc.type	Journal Article
utslib.citation.volume	77
utslib.location.activity	United States
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
utslib.copyright.status	closed_access	*
dc.date.updated	2022-10-03T21:45:26Z
pubs.issue	9
pubs.publication-status	Published
pubs.volume	77
utslib.citation.issue	9

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 ODC1 and E2F2 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 MYCN 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 MYCN, ODC1, and E2F2 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. Cancer Res; 77(9); 2522-33. ©2017 AACR.

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http://hdl.handle.net/10453/162260