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

Autor: Fabian J; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF, Heidelberg, Germany.; Phenex Pharmaceuticals AG, Waldhofer Straße, Heidelberg, Germany., Opitz D; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF, Heidelberg, Germany., Althoff K; Department of Pediatric Hematology and Oncology, University Children's Hospital Essen, Essen, Germany., Lodrini M; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF, Heidelberg, Germany.; Department of Pediatric Hematology, Oncology and SCT, Charité - University Hospital Berlin, Campus Virchow-Klinikum, Berlin, Germany., Hero B; Department of Pediatric Hematology and Oncology, University of Cologne, Cologne, Germany., Volland R; Department of Pediatric Hematology and Oncology, University of Cologne, Cologne, Germany., Beckers A; Center for Medical Genetics Ghent, Ghent University, De Pintelaan, Ghent, Belgium.; Cancer Research Institute Ghent, De Pintelaan, Ghent, Belgium., de Preter K; Center for Medical Genetics Ghent, Ghent University, De Pintelaan, Ghent, Belgium.; Cancer Research Institute Ghent, De Pintelaan, Ghent, Belgium., Decock A; Center for Medical Genetics Ghent, Ghent University, De Pintelaan, Ghent, Belgium.; Cancer Research Institute Ghent, De Pintelaan, Ghent, Belgium., Patil N; Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Centre for Biomedicine and Medical Technology, Mannheim, Germany., Abba M; Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Centre for Biomedicine and Medical Technology, Mannheim, Germany., Kopp-Schneider A; Department of Biostatistics, German Cancer Research Center (DKFZ), INF, Heidelberg, Germany., Astrahantseff K; Department of Pediatric Hematology, Oncology and SCT, Charité - University Hospital Berlin, Campus Virchow-Klinikum, Berlin, Germany., Wünschel J; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF, Heidelberg, Germany.; Department of Pediatric Hematology, Oncology and SCT, Charité - University Hospital Berlin, Campus Virchow-Klinikum, Berlin, Germany., Pfeil S; Department of Pediatric Hematology, Oncology and SCT, Charité - University Hospital Berlin, Campus Virchow-Klinikum, Berlin, Germany., Ercu M; Department of Pediatric Hematology, Oncology and SCT, Charité - University Hospital Berlin, Campus Virchow-Klinikum, Berlin, Germany., Künkele A; Department of Pediatric Hematology, Oncology and SCT, Charité - University Hospital Berlin, Campus Virchow-Klinikum, Berlin, Germany., Hu J; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF, Heidelberg, Germany.; Yale University, New Haven, CT., Thole T; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF, Heidelberg, Germany.; Department of Pediatric Hematology, Oncology and SCT, Charité - University Hospital Berlin, Campus Virchow-Klinikum, Berlin, Germany., Schweizer L; Department of Neuropathology, University of Heidelberg, INF, Heidelberg, Germany., Mechtersheimer G; Department of Pathology, University of Heidelberg, INF, Heidelberg, Germany., Carter D; Children's Cancer Institute, UNSW, Randwick, NSW, Australia., Cheung BB; Children's Cancer Institute, UNSW, Randwick, NSW, Australia., Popanda O; Division of Epigenomics and Cancer Risk Factors, DKFZ, INF, Heidelberg, Germany., von Deimling A; Department of Neuropathology, University of Heidelberg, INF, Heidelberg, Germany.; Clinical Cooperation Unit Neuropathology, DKFZ, INF, Heidelberg, Germany., Koster J; Department of Oncogenomics and Emma Children's Hospital, Academic Medical Center, University of Amster- dam, Meibergdreef, Amsterdam, the Netherlands., Versteeg R; Department of Oncogenomics and Emma Children's Hospital, Academic Medical Center, University of Amster- dam, Meibergdreef, Amsterdam, the Netherlands., Schwab M; Neuroblastoma Genetics, DKFZ, INF, Heidelberg, Germany., Marshall GM; Children's Cancer Institute, UNSW, Randwick, NSW, Australia.; Kids Cancer Centre, Sydney Children's Hospital Randwick, Randwick, NSW, Australia., Speleman F; Center for Medical Genetics Ghent, Ghent University, De Pintelaan, Ghent, Belgium.; Cancer Research Institute Ghent, De Pintelaan, Ghent, Belgium., Erb U; Experimental Surgery and Tumor Cell Biology, University of Heidelberg, INF, Heidelberg, Germany., Zoeller M; Experimental Surgery and Tumor Cell Biology, University of Heidelberg, INF, Heidelberg, Germany., Allgayer H; Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Centre for Biomedicine and Medical Technology, Mannheim, Germany., Simon T; Department of Pediatric Hematology and Oncology, University of Cologne, Cologne, Ger-many., Fischer M; Department of Pediatric Hematology and Oncology, University of Cologne, Cologne, Ger-many.; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; Max Plank Institute for Metabolism Research, Cologne, Germany., Kulozik AE; Department of Pediatric Hematology and Oncology, Heidelberg University, INF, Heidelberg, Germany., Eggert A; Department of Pediatric Hematology, Oncology and SCT, Charité - University Hospital Berlin, Campus Virchow-Klinikum, Berlin, Germany., Witt O; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF, Heidelberg, Germany.; Department of Pediatric Hematology and Oncology, Heidelberg University, INF, Heidelberg, Germany., Schulte JH; Department of Pediatric Hematology, Oncology and SCT, Charité - University Hospital Berlin, Campus Virchow-Klinikum, Berlin, Germany., Deubzer HE; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF, Heidelberg, Germany.; Department of Pediatric Hematology, Oncology and SCT, Charité - University Hospital Berlin, Campus Virchow-Klinikum, Berlin, Germany.; Department of Pediatric Hematology and Oncology, Heidelberg University, INF, Heidelberg, Germany.; Junior Neuroblastoma Research Group, Experimental and Clinical Research Center of the Max-Delbrück Center for Molecular Medicine in the Helmholtz Community and the Charité - University Medicine Berlin, Lindenberger Weg, Berlin, Germany.
Jazyk: angličtina
Zdroj: Oncotarget [Oncotarget] 2016 Oct 11; Vol. 7 (41), pp. 66344-66359.
DOI: 10.18632/oncotarget.11662
Abstrakt: 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.
Databáze: MEDLINE