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Series GSE47407 Query DataSets for GSE47407
Status Public on May 22, 2014
Title GRHL1 acts as a tumor suppressor in neuroblastoma and is negatively regulated by MYCN and HDAC3
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Neuroblastoma 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. 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 co-localized 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 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.
Overall design Twelve samples were analyzed. Each 2 replicated of paired empty vector control and GRHL1 forced expression at 3 different time points.
Contributor(s) Fabian J, Lodrini M, Oehme I, Schier MC, Thole T, Hielscher T, Kopp-Schneider A, Opitz L, Capper D, von Deimling A, Wiegand I, Milde T, Mahlknecht U, Westermann F, Popanda O, Roels F, Hero B, Berthold F, Fischer M, Kulozik AE, Witt O, Deubzer HE
Citation(s) 24419085
Submission date May 28, 2013
Last update date Aug 13, 2018
Contact name Johannes Fabian
Organization name German Cancer Research Center
Department CCU Pediatric Oncology
Street address Im Neuenheimer Feld 280
City Heidelberg
ZIP/Postal code 69120
Country Germany
Platforms (1)
GPL10558 Illumina HumanHT-12 V4.0 expression beadchip
Samples (12)
GSM1149036 empty vector 24h rep1
GSM1149037 GRHL1 24h rep1
GSM1149038 empty vector 24h rep2
BioProject PRJNA205520

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE47407_RAW.tar 26.2 Mb (http)(custom) TAR
GSE47407_non-normalized.txt.gz 5.1 Mb (ftp)(http) TXT
Processed data included within Sample table

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