Regulation of cell cycle genes and induction of senescence by overexpression of OTX2 in medulloblastoma cell lines

Bunt, Jens, de Haas, Talitha G., Hasselt, Nancy E., Zwijnenburg, Danny A., Koster, Jan, Versteeg, Rogier and Kool, Marcel (2010) Regulation of cell cycle genes and induction of senescence by overexpression of OTX2 in medulloblastoma cell lines. Molecular Cancer Research, 8 10: 1344-1357. doi:10.1158/1541-7786.MCR-09-0546

Author Bunt, Jens
de Haas, Talitha G.
Hasselt, Nancy E.
Zwijnenburg, Danny A.
Koster, Jan
Versteeg, Rogier
Kool, Marcel
Title Regulation of cell cycle genes and induction of senescence by overexpression of OTX2 in medulloblastoma cell lines
Journal name Molecular Cancer Research   Check publisher's open access policy
ISSN 1541-7786
Publication date 2010-01-01
Year available 2010
Sub-type Article (original research)
DOI 10.1158/1541-7786.MCR-09-0546
Open Access Status Not yet assessed
Volume 8
Issue 10
Start page 1344
End page 1357
Total pages 14
Place of publication Philadelphia, PA United States
Publisher American Association for Cancer Research
Language eng
Subject 1312 Molecular Biology
1306 Cancer Research
2730 Oncology
Abstract The transcription factor orthodenticle homeobox 2 (OTX2) has been implicated in the pathogenesis of medulloblastoma, as it is often highly expressed and sometimes amplified in these tumors. Little is known of the downstream pathways regulated by OTX2. We therefore generated MED8A and DAOY medulloblastoma cell lines with doxycycline-inducible OTX2 expression. In both cell lines, OTX2 inhibited proliferation and induced a senescence-like phenotype with senescence-associated β-galactosidase activity. Expression profiles of time series after OTX2 induction in MED8A showed early upregulation of cell cycle genes related to the G 2-M phase, such as AURKA, CDC25C, and CCNG2. Paradoxically, G 1-S phase genes such as MYC, CDK4, CDK6, CCND1, and CCND2 were strongly downregulated, in line with the observed G 1 arrest. ChIP-on-chip analyses of OTX2 binding to promoter regions in MED8A and DAOY showed a strong enrichment for binding to the G 2-M genes, suggesting a direct activation. Their mRNA expression correlated with OTX2 expression in primary tumors, underscoring the in vivo relevance of this regulation. OTX2 induction activated the P53 pathway in MED8A, but not in DAOY, which carries a mutated P53 gene. In DAOY cells, senescence-associated secretory factors, such as interleukin-6 and insulin-like growth factor binding protein 7, were strongly upregulated after OTX2 induction. We hypothesize that the imbalance in cell cycle stimulation by OTX2 leads to cellular senescence either by activating the P53 pathway or through the induction of secretory factors. Our data indicate that OTX2 directly induces a series of cell cycle genes but requires cooperating genes for an oncogenic acceleration of the cell cycle.
Keyword Oncology
Cell Biology
Cell Biology
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 24 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 24 Feb 2014, 01:49:48 EST by Jens Bunt on behalf of Queensland Brain Institute