TY  - JOUR
AU  - Fabian, Johannes
AU  - Opitz, Desiree Marie Irene
AU  - Althoff, Kristina
AU  - Lodrini, Marco
AU  - Hero, Barbara
AU  - Volland, Ruth
AU  - Beckers, Anneleen
AU  - de Preter, Katleen
AU  - Decock, Anneleen
AU  - Patil, Nitin
AU  - Abba, Mohammed
AU  - Kopp-Schneider, Annette
AU  - Astrahantseff, Kathy
AU  - Wünschel, Jasmin
AU  - Pfeil, Sebastian
AU  - Ercu, Maria
AU  - Künkele, Annette
AU  - Hu, Jamie
AU  - Thole, Theresa
AU  - Schweizer, Leonille
AU  - Mechtersheimer, Gunhild
AU  - Carter, Daniel
AU  - Cheung, Belamy B
AU  - Popanda, Odilia
AU  - von Deimling, Andreas
AU  - Koster, Jan
AU  - Versteeg, Rogier
AU  - Schwab, Manfred
AU  - Marshall, Glenn M
AU  - Speleman, Frank
AU  - Erb, Ulrike
AU  - Zoeller, Margot
AU  - Allgayer, Heike
AU  - Simon, Thorsten
AU  - Fischer, Matthias
AU  - Kulozik, Andreas E
AU  - Eggert, Angelika
AU  - Witt, Olaf
AU  - Schulte, Johannes H
AU  - Deubzer, Hedwig E
TI  - MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma.
JO  - OncoTarget
VL  - 7
IS  - 41
SN  - 1949-2553
CY  - [S.l.]
PB  - Impact Journals LLC
M1  - DKFZ-2017-01916
SP  - 66344 - 66359
PY  - 2016
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:27572323
C2  - pmc:PMC5341807
DO  - DOI:10.18632/oncotarget.11662
UR  - https://inrepo02.dkfz.de/record/125790
ER  -