Objective: Oxygen and its signal transduction pathways have been implicated in the control of cell proliferation and morphogenesis during the development of many tissues, including the nervous system. hASH1 (human achaete-scute homologue-1, syn: ASCL1) belongs to the family of bHLH (basic helix-loop-helix) transcription factors and is crucial for the control of neuronal differentiation. The purpose of this study is to investigate the role of oxygen in regulating hASH1 expression in neuroblastoma cells. Methods: We investigate the impact of hypoxia (0.5% oxygen vs. atmospheric conditions) on hASH1 gene expression in the human neuroblastoma-derived Kelly cell line at different time points. Protein levels were estimated by Western blotting and mRNA levels determined by qRT-PCR. The importance of potential cis-regulatory control elements is studied in reporter gene assays. Results: Hypoxia suppresses hASH1 gene expression in a time-dependent manner. Interestingly, this inhibition is observed only at the protein level, but not at the mRNA level. Reporter gene assays using constructs, in which the luciferase activity is controlled by the hASH1 mRNA untranslated regions (UTRs), reveales a posttranscriptional mechanism for down- regulation of hASH1 expression in hypoxia. Deletion of a cis-regulatory element in the hASH1 mRNA 3'UTR abolishes the suppressing influence of hypoxia on reporter gene activity. Conclusion: Hypoxic suppression of hASH1 synthesis may participate in the hypoxia-induced dedifferentiation of tumor cells, especially of neuroblastoma cells. Although the initial cellular response to low oxygen concentrations is the suppression of energy consuming processes, including mRNA translation, our data suggest that inhibition of hASH1 in hypoxia is actively controlled by cis-regulatory elements, located in the hASH1 mRNA 3'UTR.