Decitabine induces change of biological traits in myelodysplastic syndromes via FOXO1 activation

Abstract

Background: Little is known about the function of tumor suppressor gene Forkhead box 1 (FOXO1) in myelodysplastic syndromes (MDS). The aim of this study was to elucidate the role of FOXO1 through decitabine (DAC) treatment. Methods: Microarray analysis was used to identify differentially expressed genes (DEGs) from 2 MDS cell lines by DAC treatment. WebGestalt was used to perform gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) for constructing protein–protein interaction (PPI) network analysis. Cell apoptosis, cycle arrest, differentiation, and immunoregulation were performed to validate the function of FOXO1 by silencing its expression prior to DAC treatment in MDS. Results: The results showed that the FOXO signaling pathway was one of the most promising. FOXO1 exists in a hyperphosphorylated, inactive form in MDS-L cells. DAC treatment both induces FOXO1 expression and reactivates the protein through reducing its phosphorylation level. Furthermore, we showed that this FOXO1 activation is responsible for the DAC-induced apoptosis, cell cycle arrest, antigen differentiation, and immunoregulation in MDS-L cells. The results also demonstrated that DAC-induced FOXO1 activation upregulated anti-tumor immune response in higher risk MDS specimens.Conclusions: These results suggest that DAC induces FOXO1 activation, which plays an important role in anti-MDS tumors.