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

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Item Type:Article
Title:MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma
Creators Name:Fabian, J. and Opitz, D. and Althoff, K. and Lodrini, M. and Hero, B. and Volland, R. and Beckers, A. and de Preter, K. and Decock, A. and Patil, N. and Abba, M. and Kopp-Schneider, A. and Astrahantseff, K. and Wünschel, J. and Pfeil, S. and Ercu, M. and Künkele, A. and Hu, J. and Thole, T. and Schweizer, L. and Mechtersheimer, G. and Carter, D. and Cheung, B.B. and Popanda, O. and von Deimling, A. and Koster, J. and Versteeg, R. and Schwab, M. and Marshall, G.M. and Speleman, F. and Erb, U. and Zoeller, M. and Allgayer, H. and Simon, T. and Fischer, M. and Kulozik, A.E. and Eggert, A. and Witt, O. and Schulte, J.H. and Deubzer, H.E.
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.
Keywords:Antimetastatic Therapy, Chromatin Modulation, Histone Dacetylases, Grainyhead-Like Transcription Factor Family, Tetraspanin Family, Animals, Mice
Publisher:Impact Journals
Page Range:66344-66359
Date:11 October 2016
Official Publication:https://doi.org/10.18632/oncotarget.11662
PubMed:View item in PubMed

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