MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma.

Fabian, J; Opitz, D; Althoff, K; Lodrini, M; Hero, B; Volland, R; Beckers, A; de Preter, K; Decock, A; Patil, N; Abba, M; Kopp-Schneider, A; Astrahantseff, K; Wünschel, J; Pfeil, S; Ercu, M; Künkele, A; Hu, J; Thole, T; Schweizer, L; Mechtersheimer, G; Carter, D; Cheung, BB; Popanda, O; von Deimling, A; Koster, J; Versteeg, R; Schwab, M; Marshall, GM; Speleman, F; Erb, U; Zoeller, M; Allgayer, H; Simon, T; Fischer, M; Kulozik, AE; Eggert, A; Witt, O; Schulte, JH; Deubzer, HE

MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma.

Fabian, J Opitz, D Althoff, K Lodrini, M Hero, B Volland, R Beckers, A de Preter, K Decock, A Patil, N Abba, M Kopp-Schneider, A Astrahantseff, K Wünschel, J Pfeil, S Ercu, M Künkele, A Hu, J Thole, T Schweizer, L Mechtersheimer, G Carter, D

Cheung, BB Popanda, O von Deimling, A Koster, J Versteeg, R Schwab, M Marshall, GM Speleman, F Erb, U Zoeller, M Allgayer, H Simon, T Fischer, M Kulozik, AE Eggert, A Witt, O Schulte, JH Deubzer, HE

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Publisher:: IMPACT JOURNALS LLC
Publication Type:: Journal Article
Citation:: Oncotarget, 2016, 7, (41), pp. 66344-66359
Issue Date:: 2016-10-11

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Field	Value	Language
dc.contributor.author	Fabian, J
dc.contributor.author	Opitz, D
dc.contributor.author	Althoff, K
dc.contributor.author	Lodrini, M
dc.contributor.author	Hero, B
dc.contributor.author	Volland, R
dc.contributor.author	Beckers, A
dc.contributor.author	de Preter, K
dc.contributor.author	Decock, A
dc.contributor.author	Patil, N
dc.contributor.author	Abba, M
dc.contributor.author	Kopp-Schneider, A
dc.contributor.author	Astrahantseff, K
dc.contributor.author	Wünschel, J
dc.contributor.author	Pfeil, S
dc.contributor.author	Ercu, M
dc.contributor.author	Künkele, A
dc.contributor.author	Hu, J
dc.contributor.author	Thole, T
dc.contributor.author	Schweizer, L
dc.contributor.author	Mechtersheimer, G
dc.contributor.author	Carter, D https://orcid.org/0000-0002-8464-238X
dc.contributor.author	Cheung, BB
dc.contributor.author	Popanda, O
dc.contributor.author	von Deimling, A
dc.contributor.author	Koster, J
dc.contributor.author	Versteeg, R
dc.contributor.author	Schwab, M
dc.contributor.author	Marshall, GM
dc.contributor.author	Speleman, F
dc.contributor.author	Erb, U
dc.contributor.author	Zoeller, M
dc.contributor.author	Allgayer, H
dc.contributor.author	Simon, T
dc.contributor.author	Fischer, M
dc.contributor.author	Kulozik, AE
dc.contributor.author	Eggert, A
dc.contributor.author	Witt, O
dc.contributor.author	Schulte, JH
dc.contributor.author	Deubzer, HE
dc.date.accessioned	2022-08-11T02:06:45Z
dc.date.available	2016-08-24
dc.date.available	2022-08-11T02:06:45Z
dc.date.issued	2016-10-11
dc.identifier.citation	Oncotarget, 2016, 7, (41), pp. 66344-66359
dc.identifier.issn	1949-2553
dc.identifier.issn	1949-2553
dc.identifier.uri	http://hdl.handle.net/10453/159916
dc.description.abstract	The systemic and resistant nature of metastatic neuroblastoma renders it largely incurable with current multimodal treatment. Clinical progression stems mainly from the increasing burden of metastatic colonization. Therapeutically inhibiting the migration-invasion-metastasis cascade would be of great benefit, but the mechanisms driving this cycle are as yet poorly understood. In-depth transcriptome analyses and ChIP-qPCR identified the cell surface glycoprotein, CD9, as a major downstream player and direct target of the recently described GRHL1 tumor suppressor. CD9 is known to block or facilitate cancer cell motility and metastasis dependent upon entity. High-level CD9 expression in primary neuroblastomas correlated with patient survival and established markers for favorable disease. Low-level CD9 expression was an independent risk factor for adverse outcome. MYCN and HDAC5 colocalized to the CD9 promoter and repressed transcription. CD9 expression diminished with progressive tumor development in the TH-MYCN transgenic mouse model for neuroblastoma, and CD9 expression in neuroblastic tumors was far below that in ganglia from wildtype mice. Primary neuroblastomas lacking MYCN amplifications displayed differential CD9 promoter methylation in methyl-CpG-binding domain sequencing analyses, and high-level methylation was associated with advanced stage disease, supporting epigenetic regulation. Inducing CD9 expression in a SH-EP cell model inhibited migration and invasion in Boyden chamber assays. Enforced CD9 expression in neuroblastoma cells transplanted onto chicken chorioallantoic membranes strongly reduced metastasis to embryonic bone marrow. Combined treatment of neuroblastoma cells with HDAC/DNA methyltransferase inhibitors synergistically induced CD9 expression despite hypoxic, metabolic or cytotoxic stress. Our results show CD9 is a critical and indirectly druggable suppressor of the invasion-metastasis cycle in neuroblastoma.
dc.format	Print
dc.language	eng
dc.publisher	IMPACT JOURNALS LLC
dc.relation.ispartof	Oncotarget
dc.relation.isbasedon	10.18632/oncotarget.11662
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.mesh	Animals
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Histone Deacetylases
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Tetraspanin 29
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	Histone Deacetylases
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Tetraspanin 29
dc.title	MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma.
dc.type	Journal Article
utslib.citation.volume	7
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/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	closed_access	*
dc.date.updated	2022-08-11T02:06:41Z
pubs.issue	41
pubs.publication-status	Published
pubs.volume	7
utslib.citation.issue	41

Abstract:

The systemic and resistant nature of metastatic neuroblastoma renders it largely incurable with current multimodal treatment. Clinical progression stems mainly from the increasing burden of metastatic colonization. Therapeutically inhibiting the migration-invasion-metastasis cascade would be of great benefit, but the mechanisms driving this cycle are as yet poorly understood. In-depth transcriptome analyses and ChIP-qPCR identified the cell surface glycoprotein, CD9, as a major downstream player and direct target of the recently described GRHL1 tumor suppressor. CD9 is known to block or facilitate cancer cell motility and metastasis dependent upon entity. High-level CD9 expression in primary neuroblastomas correlated with patient survival and established markers for favorable disease. Low-level CD9 expression was an independent risk factor for adverse outcome. MYCN and HDAC5 colocalized to the CD9 promoter and repressed transcription. CD9 expression diminished with progressive tumor development in the TH-MYCN transgenic mouse model for neuroblastoma, and CD9 expression in neuroblastic tumors was far below that in ganglia from wildtype mice. Primary neuroblastomas lacking MYCN amplifications displayed differential CD9 promoter methylation in methyl-CpG-binding domain sequencing analyses, and high-level methylation was associated with advanced stage disease, supporting epigenetic regulation. Inducing CD9 expression in a SH-EP cell model inhibited migration and invasion in Boyden chamber assays. Enforced CD9 expression in neuroblastoma cells transplanted onto chicken chorioallantoic membranes strongly reduced metastasis to embryonic bone marrow. Combined treatment of neuroblastoma cells with HDAC/DNA methyltransferase inhibitors synergistically induced CD9 expression despite hypoxic, metabolic or cytotoxic stress. Our results show CD9 is a critical and indirectly druggable suppressor of the invasion-metastasis cycle in neuroblastoma.

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http://hdl.handle.net/10453/159916