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@ARTICLE{Fabian:125790,
author = {J. Fabian$^*$ and D. M. I. Opitz$^*$ and K. Althoff and M.
Lodrini$^*$ and B. Hero and R. Volland and A. Beckers and K.
de Preter and A. Decock and N. Patil and M. Abba and A.
Kopp-Schneider$^*$ and K. Astrahantseff and J. Wünschel$^*$
and S. Pfeil and M. Ercu and A. Künkele and J. Hu$^*$ and
T. Thole$^*$ and L. Schweizer and G. Mechtersheimer and D.
Carter and B. B. Cheung and O. Popanda and A. von
Deimling$^*$ and J. Koster and R. Versteeg and M. Schwab and
G. M. Marshall and F. Speleman and U. Erb and M. Zoeller and
H. Allgayer and T. Simon and M. Fischer and A. E. Kulozik
and A. Eggert and O. Witt$^*$ and J. H. Schulte and H. E.
Deubzer$^*$},
title = {{MYCN} and {HDAC}5 transcriptionally repress {CD}9 to
trigger invasion and metastasis in neuroblastoma.},
journal = {OncoTarget},
volume = {7},
number = {41},
issn = {1949-2553},
address = {[S.l.]},
publisher = {Impact Journals LLC},
reportid = {DKFZ-2017-01916},
pages = {66344 - 66359},
year = {2016},
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.},
cin = {G340 / C060 / C010 / L101 / L201},
ddc = {610},
cid = {I:(DE-He78)G340-20160331 / I:(DE-He78)C060-20160331 /
I:(DE-He78)C010-20160331 / I:(DE-He78)L101-20160331 /
I:(DE-He78)L201-20160331},
pnm = {317 - Translational cancer research (POF3-317)},
pid = {G:(DE-HGF)POF3-317},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:27572323},
pmc = {pmc:PMC5341807},
doi = {10.18632/oncotarget.11662},
url = {https://inrepo02.dkfz.de/record/125790},
}