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| Status |
Public on Dec 31, 2014 |
| Title |
Stimulating BMP4 signaling via HDAC11 inhibition suppresses malignancy in preclinical models of human neuroblastoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Bone morphogenetic proteins (BMPs) trigger as cell-extrinsic signals the differentiation of neural crest progenitor cells to the sympathoadrenal cell lineage. Human neuroblastoma derives from aberrant neural crest progenitor cells. We here show that histone deacetylase 11 (HDAC11), the most recently identified family member with, as yet, largely unknown function, is recruited to the BMP4 gene promoter and represses its transcription in neuroblastoma. Both HDAC11 depletion and enzymatic inhibition revert the epigenetic silencing of BMP4, thereby blocking a critical oncogenic function of HDAC11. Activated BMP4 signaling through targeting of HDAC11 induces a transcriptional profile predictive of favorable prognosis for patients when expressed in the tumors, indicating that the HDAC11-BMP4 axis plays a critical role for neuroblastoma biology. Furthermore, pathway activation causes MYCN proto-oncogene repression on a molecular level and anti-proliferative effects in functional assays in neuroblastoma cell lines and primary sphere cultures as well as strongly inhibiting tumor formation and growth of subcutaneous neuroblastoma xenografts in mice. For high-risk neuroblastoma, with cure rates below 30% using current treatment strategies, our work suggests a novel targeted therapeutic approach that would reactivate the developmental pathway inducing normal differentiation of neural crest progenitor cells.
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| Overall design |
Agilent data: Common Reference Design with 48 chips including 17 different samples with 3 replicates per sample.
Illumina data: BE(2)C neuroblastoma cells were transfected with siRNAs against HDAC11 for 48h, and 96h, respectively. As controls served siRNA transfection with scrambled siRNAs. In parallel, cells were treated for 72h with the pan-HDAC inhibitor HC-toxin. As control for HC-Toxin, cells were tretaed with MeOH solvent. All experiments were performed in triplicates. RNA was prepared from cell lysates using RNeasy (Qiagen) according to manufacturer's instruction. standard procedures. RNA quality was checked with Agilent Bioanalyzer.
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| Contributor(s) |
Deubzer HE, Lodrini M, Milde T, Schier MC, Oehme I, Schulte JH, Thole T, Fabian J, Wiegand I, vonDeimling A, Opitz L, Astrahantseff K, Schramm A, Michaelis M, Brors B, Fischer M, Eggert A, Kulozik AE, Witt O |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Feb 17, 2010 |
| Last update date |
Mar 20, 2017 |
| Contact name |
Gabriela Salinas |
| E-mail(s) |
Gabriela.Salinas-Riester@medizin.uni-goettingen.de
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| Organization name |
Universitaetsmedizin Goettingen
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| Department |
Department of Human Genetics
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| Lab |
NGS Integrative Genomics
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| Street address |
Justus-von-Liebig-Weg 11
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| City |
Goettingen |
| State/province |
Lower-Saxony |
| ZIP/Postal code |
37077 |
| Country |
Germany |
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| Platforms (2) |
| GPL6883 |
Illumina HumanRef-8 v3.0 expression beadchip |
| GPL16301 |
Agilent-012391 Human Microarray (012391_D_F_20091216) |
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| Samples (66)
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| Relations |
| BioProject |
PRJNA125531 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE20399_RAW.tar |
204.0 Mb |
(http)(custom) |
TAR (of TXT) |
| GSE20399_non-normalized.txt.gz |
3.7 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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