4.4 Article

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

Journal

MOLECULAR BIOLOGY OF THE CELL
Volume 23, Issue 11, Pages 2226-2234

Publisher

AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E11-06-0535

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Funding

  1. Competence Centers for Excellent Technologies
  2. Center for Personalized Cancer Medicine
  3. Austrian Federal Ministry for Transport, Innovation and Technology/Ministry of Economy, Family and Youth (via the Austrian Research Promotion Agency)
  4. Tiroler Zukunftsstiftung/Standortagentur Tirol
  5. Kinderkrebshilfe Tirol und Vorarlberg
  6. SVP-Frauen-Initiative
  7. Krebshilfe Sudtirol
  8. Kinderkrebshilfe Sudtirol-Regenbogen
  9. Tiroler Landeskrankenanstalten
  10. Tyrolean Cancer Society
  11. Department of Health Care, Autonomous Province of South Tyrol

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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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