OTX2 directly activates cell cycle genes and inhibits differentiation in medulloblastoma cells

Bunt, J., Hasselt, N. E., Zwijnenburg, D. A., Hamdi, M., Koster, J., Versteeg, R. and Kool, M. (2012) OTX2 directly activates cell cycle genes and inhibits differentiation in medulloblastoma cells. International Journal of Cancer, 131 2: E21-E32. doi:10.1002/ijc.26474


Author Bunt, J.
Hasselt, N. E.
Zwijnenburg, D. A.
Hamdi, M.
Koster, J.
Versteeg, R.
Kool, M.
Title OTX2 directly activates cell cycle genes and inhibits differentiation in medulloblastoma cells
Journal name International Journal of Cancer   Check publisher's open access policy
ISSN 0020-7136
1097-0215
Publication date 2012-07-15
Year available 2012
Sub-type Article (original research)
DOI 10.1002/ijc.26474
Open Access Status
Volume 131
Issue 2
Start page E21
End page E32
Total pages 12
Place of publication Hoboken, NJ, United States
Publisher John Wiley and Sons
Collection year 2013
Language eng
Abstract The transcription factor OTX2 has been implicated as an oncogene in medulloblastoma, which is the most common malignant brain tumor in children. It is highly expressed in most medulloblastomas and amplified in a subset of them. To study the role OTX2 has in medulloblastoma we investigated the downstream pathway of OTX2. We generated D425 medulloblastoma cells in which endogenous OTX2 can be silenced by inducible shRNA. Silencing of OTX2 strongly inhibited cell proliferation and resulted in a neuronal-like differentiation. Expression profiling of time courses after silencing showed a progressive change in gene expression for many cellular processes. Downregulated genes were highly enriched for cell cycle and visual perception genes, while upregulated genes were enriched for genes involved in development and differentiation. This shift is reminiscent of expression changes described during normal cerebellum development where proliferating granule progenitor cells have high OTX2 expression, which diminishes when these cells exit the cell cycle and start to differentiate. ChIP-on-chip analyses of OTX2 in D425 cells identified cell cycle and perception genes as direct OTX2 targets, while regulation of most differentiation genes appeared to be indirect. The expression of many directly regulated genes correlated to OTX2 expression in primary tumors, suggesting the in vivo relevance of these genes and their potential as targets for therapeutic intervention. These analyses provide more insight in the molecular network of OTX2, demonstrating that OTX2 is essential in medulloblastoma and directly drives proliferation by regulation of cell cycle genes. Copyright
Keyword Chromatin
Expression Profiling
Immunoprecipitation
Medulloblastoma
OTX2
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
Queensland Brain Institute Publications
 
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Created: Sun, 23 Feb 2014, 15:51:34 EST by Jens Bunt on behalf of Queensland Brain Institute