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000125790 1001_ $$0P:(DE-HGF)0$$aFabian, Johannes$$b0$$eFirst author
000125790 245__ $$aMYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma.
000125790 260__ $$a[S.l.]$$bImpact Journals LLC$$c2016
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000125790 520__ $$aThe 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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000125790 7001_ $$0P:(DE-He78)72f81373ed4ff22e341bd56b00f31479$$aOpitz, Desiree Marie Irene$$b1$$udkfz
000125790 7001_ $$aAlthoff, Kristina$$b2
000125790 7001_ $$0P:(DE-HGF)0$$aLodrini, Marco$$b3
000125790 7001_ $$aHero, Barbara$$b4
000125790 7001_ $$aVolland, Ruth$$b5
000125790 7001_ $$aBeckers, Anneleen$$b6
000125790 7001_ $$ade Preter, Katleen$$b7
000125790 7001_ $$aDecock, Anneleen$$b8
000125790 7001_ $$aPatil, Nitin$$b9
000125790 7001_ $$aAbba, Mohammed$$b10
000125790 7001_ $$0P:(DE-He78)bb6a7a70f976eb8df1769944bf913596$$aKopp-Schneider, Annette$$b11$$udkfz
000125790 7001_ $$aAstrahantseff, Kathy$$b12
000125790 7001_ $$0P:(DE-HGF)0$$aWünschel, Jasmin$$b13
000125790 7001_ $$aPfeil, Sebastian$$b14
000125790 7001_ $$aErcu, Maria$$b15
000125790 7001_ $$aKünkele, Annette$$b16
000125790 7001_ $$0P:(DE-HGF)0$$aHu, Jamie$$b17
000125790 7001_ $$0P:(DE-He78)08b90069c7cb74d14939106d2a1fac13$$aThole, Theresa$$b18$$udkfz
000125790 7001_ $$aSchweizer, Leonille$$b19
000125790 7001_ $$aMechtersheimer, Gunhild$$b20
000125790 7001_ $$aCarter, Daniel$$b21
000125790 7001_ $$aCheung, Belamy B$$b22
000125790 7001_ $$aPopanda, Odilia$$b23
000125790 7001_ $$0P:(DE-He78)a8a10626a848d31e70cfd96a133cc144$$avon Deimling, Andreas$$b24$$udkfz
000125790 7001_ $$aKoster, Jan$$b25
000125790 7001_ $$aVersteeg, Rogier$$b26
000125790 7001_ $$aSchwab, Manfred$$b27
000125790 7001_ $$aMarshall, Glenn M$$b28
000125790 7001_ $$aSpeleman, Frank$$b29
000125790 7001_ $$aErb, Ulrike$$b30
000125790 7001_ $$aZoeller, Margot$$b31
000125790 7001_ $$aAllgayer, Heike$$b32
000125790 7001_ $$aSimon, Thorsten$$b33
000125790 7001_ $$aFischer, Matthias$$b34
000125790 7001_ $$aKulozik, Andreas E$$b35
000125790 7001_ $$aEggert, Angelika$$b36
000125790 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, Olaf$$b37$$udkfz
000125790 7001_ $$aSchulte, Johannes H$$b38
000125790 7001_ $$0P:(DE-HGF)0$$aDeubzer, Hedwig E$$b39$$eLast author
000125790 773__ $$0PERI:(DE-600)2560162-3$$a10.18632/oncotarget.11662$$gVol. 7, no. 41, p. 66344 - 66359$$n41$$p66344 - 66359$$tOncoTarget$$v7$$x1949-2553$$y2016
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