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000119916 0247_ $$2ISSN$$a0099-7013
000119916 0247_ $$2ISSN$$a0099-7374
000119916 0247_ $$2ISSN$$a1538-7445
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000119916 1001_ $$0P:(DE-HGF)0$$aFabian, Johannes$$b0$$eFirst author
000119916 245__ $$aGRHL1 acts as tumor suppressor in neuroblastoma and is negatively regulated by MYCN and HDAC3.
000119916 260__ $$aPhiladelphia, Pa.$$bAACR$$c2014
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000119916 520__ $$aNeuroblastoma is an embryonic solid tumor of neural crest origin and accounts for 11% of all cancer-related deaths in children. Novel therapeutic strategies are therefore urgently required. MYCN oncogene amplification, which occurs in 20% of neuroblastomas, is a hallmark of high risk. Here, we aimed to exploit molecular mechanisms that can be pharmacologically addressed with epigenetically modifying drugs, such as histone deacetylase (HDAC) inhibitors. Grainyhead-like 1 (GRHL1), a gene critical for Drosophila neural development, belonged to the genes most strongly responding to HDAC inhibitor treatment of neuroblastoma cells in a genome-wide screen. An increase in the histone H4 pan-acetylation associated with its promoter preceded transcriptional activation. Physically adjacent, HDAC3 and MYCN colocalized to the GRHL1 promoter and repressed its transcription. High-level GRHL1 expression in primary neuroblastomas correlated on transcriptional and translational levels with favorable patient survival and established clinical and molecular markers for favorable tumor biology, including lack of MYCN amplification. Enforced GRHL1 expression in MYCN-amplified neuroblastoma cells with low endogenous GRHL1 levels abrogated anchorage-independent colony formation, inhibited proliferation, and retarded xenograft growth in mice. GRHL1 knockdown in MYCN single-copy cells with high endogenous GRHL1 levels promoted colony formation. GRHL1 regulated 170 genes genome-wide, and most were involved in pathways regulated during neuroblastomagenesis, including nervous system development, proliferation, cell-cell adhesion, cell spreading, and cellular differentiation. In summary, the data presented here indicate a significant role of HDAC3 in the MYCN-mediated repression of GRHL1 and suggest drugs that block HDAC3 activity and suppress MYCN expression as promising candidates for novel treatment strategies of high-risk neuroblastoma.
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000119916 650_7 $$2NLM Chemicals$$aAntineoplastic Agents
000119916 650_7 $$2NLM Chemicals$$aGRHL1 protein, human
000119916 650_7 $$2NLM Chemicals$$aHistone Deacetylase Inhibitors
000119916 650_7 $$2NLM Chemicals$$aHydroxamic Acids
000119916 650_7 $$2NLM Chemicals$$aIndoles
000119916 650_7 $$2NLM Chemicals$$aMYCN protein, human
000119916 650_7 $$2NLM Chemicals$$aN-Myc Proto-Oncogene Protein
000119916 650_7 $$2NLM Chemicals$$aNuclear Proteins
000119916 650_7 $$2NLM Chemicals$$aOncogene Proteins
000119916 650_7 $$2NLM Chemicals$$aRepressor Proteins
000119916 650_7 $$09647FM7Y3Z$$2NLM Chemicals$$apanobinostat
000119916 650_7 $$0EC 3.5.1.98$$2NLM Chemicals$$aHistone Deacetylases
000119916 650_7 $$0EC 3.5.1.98$$2NLM Chemicals$$ahistone deacetylase 3
000119916 7001_ $$0P:(DE-HGF)0$$aLodrini, Marco$$b1
000119916 7001_ $$0P:(DE-He78)908367a659dea9e28dac34592b3c46e5$$aOehme, Ina$$b2$$udkfz
000119916 7001_ $$0P:(DE-HGF)0$$aSchier, Marie C$$b3
000119916 7001_ $$0P:(DE-He78)08b90069c7cb74d14939106d2a1fac13$$aThole, Theresa$$b4$$udkfz
000119916 7001_ $$0P:(DE-He78)743a4a82daab55306a2c88b9f6bf8c2f$$aHielscher, Thomas$$b5$$udkfz
000119916 7001_ $$0P:(DE-He78)bb6a7a70f976eb8df1769944bf913596$$aKopp-Schneider, Annette$$b6$$udkfz
000119916 7001_ $$aOpitz, Lennart$$b7
000119916 7001_ $$0P:(DE-He78)51bf9ae9cb5771b30c483e5597ef606c$$aCapper, David$$b8$$udkfz
000119916 7001_ $$0P:(DE-He78)a8a10626a848d31e70cfd96a133cc144$$avon Deimling, Andreas$$b9$$udkfz
000119916 7001_ $$0P:(DE-HGF)0$$aWiegand, Inga$$b10
000119916 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b11$$udkfz
000119916 7001_ $$aMahlknecht, Ulrich$$b12
000119916 7001_ $$0P:(DE-He78)91f32735ee876c579d63c05a7f4778dd$$aWestermann, Frank$$b13$$udkfz
000119916 7001_ $$0P:(DE-He78)37610ef78c733753f0836ce0e41b9fda$$aPopanda, Odilia$$b14$$udkfz
000119916 7001_ $$aRoels, Frederik$$b15
000119916 7001_ $$aHero, Barbara$$b16
000119916 7001_ $$aBerthold, Frank$$b17
000119916 7001_ $$aFischer, Matthias$$b18
000119916 7001_ $$aKulozik, Andreas E$$b19
000119916 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, Olaf$$b20$$udkfz
000119916 7001_ $$0P:(DE-HGF)0$$aDeubzer, Hedwig E$$b21$$eLast author
000119916 773__ $$0PERI:(DE-600)2036785-5$$a10.1158/0008-5472.CAN-13-1904$$gVol. 74, no. 9, p. 2604 - 2616$$n9$$p2604 - 2616$$tCancer research$$v74$$x1538-7445$$y2014
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