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

Johannes Fabian, Desirée Opitz, Kristina Althoff, Marco Lodrini, Barbara Hero, Ruth Volland, Anneleen Beckers, Katleen De Preter UGent, Anneleen Decock UGent, Nitin Patil, et al. (2016) ONCOTARGET. 7(41). p.66344-66359
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
antimetastatic therapy, chromatin modulation, histone deacetylases, grainyhead-like transcription factor family, tetraspanin family, HIGH-RISK NEUROBLASTOMA, ACTIVATING MUTATIONS, ALK KINASE, N-MYC, EXPRESSION, GENE, DIFFERENTIATION, CLASSIFICATION, REARRANGEMENTS, ASSOCIATION
journal title
ONCOTARGET
Oncotarget
volume
7
issue
41
pages
66344 - 66359
Web of Science type
Article
Web of Science id
000387446200005
JCR category
ONCOLOGY
JCR impact factor
5.168 (2016)
JCR rank
44/217 (2016)
JCR quartile
1 (2016)
ISSN
1949-2553
DOI
10.18632/oncotarget.11662
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
8060888
handle
http://hdl.handle.net/1854/LU-8060888
date created
2016-09-05 15:36:39
date last changed
2017-04-13 09:41:29
@article{8060888,
  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.},
  author       = {Fabian, Johannes and Opitz, Desir{\'e}e and Althoff, Kristina and Lodrini, Marco and Hero, Barbara and Volland, Ruth and Beckers, Anneleen and De Preter, Katleen and Decock, Anneleen and Patil, Nitin and Abba, Mohammed and Kopp-Schneider, Annette and Astrahantseff, Kathy and W{\"u}nschel, Jasmin and Pfeil, Sebastian and Ercu, Maria and K{\"u}nkele, Annette and Hu, Jamie and Thole, Theresa and Schweizer, Leonille and Mechtersheimer, Gunhild and Carter, Daniel and Cheung, Belamy B and Popanda, Odilia and v. Deimling, Andreas and Koster, Jan and Versteeg, Rogier and Schwab, Manfred and Marshall, Glenn M and Speleman, Franki and Erb, Ulrike and Zoeller, Margot and Allgayer, Heike and Simon, Thorsten and Fischer, Matthias and Kulozik, Andreas E and Eggert, Angelika and Witt, Olaf and Schulte, Johannes H and Deubzer, Hedwig E},
  issn         = {1949-2553},
  journal      = {ONCOTARGET},
  keyword      = {antimetastatic therapy,chromatin modulation,histone deacetylases,grainyhead-like transcription factor family,tetraspanin family,HIGH-RISK NEUROBLASTOMA,ACTIVATING MUTATIONS,ALK KINASE,N-MYC,EXPRESSION,GENE,DIFFERENTIATION,CLASSIFICATION,REARRANGEMENTS,ASSOCIATION},
  language     = {eng},
  number       = {41},
  pages        = {66344--66359},
  title        = {MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma},
  url          = {http://dx.doi.org/10.18632/oncotarget.11662},
  volume       = {7},
  year         = {2016},
}

Chicago
Fabian, Johannes, Desirée Opitz, Kristina Althoff, Marco Lodrini, Barbara Hero, Ruth Volland, Anneleen Beckers, et al. 2016. “MYCN and HDAC5 Transcriptionally Repress CD9 to Trigger Invasion and Metastasis in Neuroblastoma.” Oncotarget 7 (41): 66344–66359.
APA
Fabian, J., Opitz, D., Althoff, K., Lodrini, M., Hero, B., Volland, R., Beckers, A., et al. (2016). MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma. ONCOTARGET, 7(41), 66344–66359.
Vancouver
1.
Fabian J, Opitz D, Althoff K, Lodrini M, Hero B, Volland R, et al. MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma. ONCOTARGET. 2016;7(41):66344–59.
MLA
Fabian, Johannes, Desirée Opitz, Kristina Althoff, et al. “MYCN and HDAC5 Transcriptionally Repress CD9 to Trigger Invasion and Metastasis in Neuroblastoma.” ONCOTARGET 7.41 (2016): 66344–66359. Print.