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FOXO3/FKHRL1 is activated by 5-aza-2-deoxycytidine and induces silenced caspase-8 in neuroblastoma

Forkhead box O (FOXO) transcription factors control diverse cellular functions, such as cell death, metabolism, and longevity. We analyzed FOXO3/FKHRL1 expression and subcellular localization in tumor sections of neuroblastoma patients and observed a correlation between nuclear FOXO3 and high caspas...

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Autores principales: Geiger, Kathrin, Hagenbuchner, Judith, Rupp, Martina, Fiegl, Heidi, Sergi, Consolato, Meister, Bernhard, Kiechl-Kohlendorfer, Ursula, Müller, Thomas, Ausserlechner, Michael J., Obexer, Petra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364184/
https://www.ncbi.nlm.nih.gov/pubmed/22493319
http://dx.doi.org/10.1091/mbc.E11-06-0535
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author Geiger, Kathrin
Hagenbuchner, Judith
Rupp, Martina
Fiegl, Heidi
Sergi, Consolato
Meister, Bernhard
Kiechl-Kohlendorfer, Ursula
Müller, Thomas
Ausserlechner, Michael J.
Obexer, Petra
author_facet Geiger, Kathrin
Hagenbuchner, Judith
Rupp, Martina
Fiegl, Heidi
Sergi, Consolato
Meister, Bernhard
Kiechl-Kohlendorfer, Ursula
Müller, Thomas
Ausserlechner, Michael J.
Obexer, Petra
author_sort Geiger, Kathrin
collection PubMed
description Forkhead box O (FOXO) transcription factors control diverse cellular functions, such as cell death, metabolism, and longevity. We analyzed FOXO3/FKHRL1 expression and subcellular localization in tumor sections of neuroblastoma patients and observed a correlation between nuclear FOXO3 and high caspase-8 expression. In neuroblastoma caspase-8 is frequently silenced by DNA methylation. Conditional FOXO3 activated caspase-8 gene expression but did not change the DNA-methylation pattern of regulatory sequences in the caspase-8 gene. Instead, FOXO3 induced phosphorylation of its binding partner ATM and of the ATM downstream target cAMP-responsive element binding protein (CREB), which was critical for FOXO3-mediated caspase-8 expression. Caspase-8 levels above a critical threshold sensitized neuroblastoma cells to tumor necrosis factor–related apoptosis-inducing ligand–induced cell death. The DNA-demethylating drug 5-Aza-2-deoxycytidine (5-azadC) induced rapid nuclear accumulation of FOXO3, ATM-dependent CREB phosphorylation, and caspase-8 expression in a FOXO3-dependent manner. This indicates that 5-azadC activates the FOXO3-ATM-CREB signaling pathway, which contributes to caspase-8 expression. The combined data suggest that FOXO3 is activated by 5-azadC treatment and triggers expression of caspase-8 in caspase-8–negative neuroblastoma, which may have important implication for metastasis, therapy, and death resistance of this childhood malignancy.
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spelling pubmed-33641842012-08-16 FOXO3/FKHRL1 is activated by 5-aza-2-deoxycytidine and induces silenced caspase-8 in neuroblastoma Geiger, Kathrin Hagenbuchner, Judith Rupp, Martina Fiegl, Heidi Sergi, Consolato Meister, Bernhard Kiechl-Kohlendorfer, Ursula Müller, Thomas Ausserlechner, Michael J. Obexer, Petra Mol Biol Cell Articles Forkhead box O (FOXO) transcription factors control diverse cellular functions, such as cell death, metabolism, and longevity. We analyzed FOXO3/FKHRL1 expression and subcellular localization in tumor sections of neuroblastoma patients and observed a correlation between nuclear FOXO3 and high caspase-8 expression. In neuroblastoma caspase-8 is frequently silenced by DNA methylation. Conditional FOXO3 activated caspase-8 gene expression but did not change the DNA-methylation pattern of regulatory sequences in the caspase-8 gene. Instead, FOXO3 induced phosphorylation of its binding partner ATM and of the ATM downstream target cAMP-responsive element binding protein (CREB), which was critical for FOXO3-mediated caspase-8 expression. Caspase-8 levels above a critical threshold sensitized neuroblastoma cells to tumor necrosis factor–related apoptosis-inducing ligand–induced cell death. The DNA-demethylating drug 5-Aza-2-deoxycytidine (5-azadC) induced rapid nuclear accumulation of FOXO3, ATM-dependent CREB phosphorylation, and caspase-8 expression in a FOXO3-dependent manner. This indicates that 5-azadC activates the FOXO3-ATM-CREB signaling pathway, which contributes to caspase-8 expression. The combined data suggest that FOXO3 is activated by 5-azadC treatment and triggers expression of caspase-8 in caspase-8–negative neuroblastoma, which may have important implication for metastasis, therapy, and death resistance of this childhood malignancy. The American Society for Cell Biology 2012-06-01 /pmc/articles/PMC3364184/ /pubmed/22493319 http://dx.doi.org/10.1091/mbc.E11-06-0535 Text en © 2012 Geiger et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Geiger, Kathrin
Hagenbuchner, Judith
Rupp, Martina
Fiegl, Heidi
Sergi, Consolato
Meister, Bernhard
Kiechl-Kohlendorfer, Ursula
Müller, Thomas
Ausserlechner, Michael J.
Obexer, Petra
FOXO3/FKHRL1 is activated by 5-aza-2-deoxycytidine and induces silenced caspase-8 in neuroblastoma
title FOXO3/FKHRL1 is activated by 5-aza-2-deoxycytidine and induces silenced caspase-8 in neuroblastoma
title_full FOXO3/FKHRL1 is activated by 5-aza-2-deoxycytidine and induces silenced caspase-8 in neuroblastoma
title_fullStr FOXO3/FKHRL1 is activated by 5-aza-2-deoxycytidine and induces silenced caspase-8 in neuroblastoma
title_full_unstemmed FOXO3/FKHRL1 is activated by 5-aza-2-deoxycytidine and induces silenced caspase-8 in neuroblastoma
title_short FOXO3/FKHRL1 is activated by 5-aza-2-deoxycytidine and induces silenced caspase-8 in neuroblastoma
title_sort foxo3/fkhrl1 is activated by 5-aza-2-deoxycytidine and induces silenced caspase-8 in neuroblastoma
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364184/
https://www.ncbi.nlm.nih.gov/pubmed/22493319
http://dx.doi.org/10.1091/mbc.E11-06-0535
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