Fabian, Johannes, Opitz, Desiree, Althoff, Kristina, Lodrini, Marco, Hero, Barbara, Volland, Ruth, Beckers, Anneleen, de Preter, Katleen, Decock, Anneleen ORCID: 0000-0002-1091-0927, Patil, Nitin, Abba, Mohammed, Kopp-Schneider, Annette, Astrahantseff, Kathy, Wuenschel, Jasmin, Pfeil, Sebastian, Ercu, Maria, Kuenkele, Annette, Hu, Jamie, Thole, Theresa, Schweizer, Leonille, Mechtersheimer, Gunhild, Carter, Daniel ORCID: 0000-0002-8464-238X, Cheung, Belamy B., Popanda, Odilia, v. Deimling, Andreas, Koster, Jan ORCID: 0000-0002-0890-7585, Versteeg, Rogier ORCID: 0000-0001-7172-0388, Schwab, Manfred, Marshall, Glenn M., Speleman, Frank, Erb, Ulrike, Zoeller, Margot, Allgayer, Heike, Simon, Thorsten, Fischer, Matthias, Kulozik, Andreas E., Eggert, Angelika, Witt, Olaf, Schulte, Johannes H. and Deubzer, Hedwig E. (2016). MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma. Oncotarget, 7 (41). S. 66344 - 66360. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Fabian, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Opitz, DesireeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Althoff, KristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lodrini, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hero, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Volland, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beckers, AnneleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Preter, KatleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Decock, AnneleenUNSPECIFIEDorcid.org/0000-0002-1091-0927UNSPECIFIED
Patil, NitinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abba, MohammedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kopp-Schneider, AnnetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Astrahantseff, KathyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wuenschel, JasminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfeil, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ercu, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuenkele, AnnetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hu, JamieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thole, TheresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweizer, LeonilleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mechtersheimer, GunhildUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carter, DanielUNSPECIFIEDorcid.org/0000-0002-8464-238XUNSPECIFIED
Cheung, Belamy B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Popanda, OdiliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
v. Deimling, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koster, JanUNSPECIFIEDorcid.org/0000-0002-0890-7585UNSPECIFIED
Versteeg, RogierUNSPECIFIEDorcid.org/0000-0001-7172-0388UNSPECIFIED
Schwab, ManfredUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marshall, Glenn M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Speleman, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erb, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zoeller, MargotUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allgayer, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simon, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kulozik, Andreas E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eggert, AngelikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witt, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, Johannes H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deubzer, Hedwig E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-258432
DOI: 10.18632/oncotarget.11662
Journal or Publication Title: Oncotarget
Volume: 7
Number: 41
Page Range: S. 66344 - 66360
Date: 2016
Publisher: IMPACT JOURNALS LLC
Place of Publication: ORCHARD PARK
ISSN: 1949-2553
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ACTIVATING MUTATIONS; ALK KINASE; EXPRESSION; CLASSIFICATION; REARRANGEMENTS; ASSOCIATION; SUPPRESSOR; TARGETMultiple languages
Oncology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/25843

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