Abstract
Decitabine (DAC) is considered to be a profound global DNA demethylation, which can induce the re-expression of silenced tumor suppressor genes. Little is known about the function of tumor suppressor gene FOXO1 in myelodysplastic syndromes (MDS). To address this issue, the study firstly investigated differentially expressed genes (DEGs) for DAC treatment in MDS cell lines, then explored the role of FOXO1 through silencing its expression before DAC treatment in MDS. The results showed that FOXO1 exists in a hyperphosphorylated, inactive form in MDS-L cells. DAC treatment both induces FOXO1 expression and reactivates the protein in its low phosphorylation level. Additionally, the results also demonstrated that this FOXO1 activation is responsible for the DAC-induced apoptosis, cell cycle arrest, antigen differentiation, and immunoregulation in MDS-L cells. We also demonstrated DAC-induced FOXO1 activation upregulates anti-tumor immune response in higher-risk MDS specimens. Collectively, these results suggest that DAC induces FOXO1 activation, which plays an important role in anti-MDS tumors.
Highlights
Myelodysplastic syndrome (MDS) is a set of highly heterogeneous myeloid neoplasms, featured by variable cytopenias, inefficient hematopoiesis and a proportionable risk of progression to acute myeloid leukemia
The gene ontology (GO) analysis revealed that MDS cell line differentially expressed genes (DEGs) are involved in the process of immune-related response
For cellular component (CC), enrichment of DEGs was mainly enriched inside the chromosome, chromosomal part, and nuclear chromosome (Figure 1B)
Summary
Myelodysplastic syndrome (MDS) is a set of highly heterogeneous myeloid neoplasms, featured by variable cytopenias, inefficient hematopoiesis and a proportionable risk of progression to acute myeloid leukemia. Hypomethylating agents (HMAs), such as decitabine (DAC), are approved as the first-line treatment option for higher- risk MDS. DAC has a wide range of therapeutic mechanisms for MDS, which reactivates silenced tumor suppressor genes, increases expression of cancer-testis antigens (CTAs), and regulates immune checkpoint molecules (Chang et al, 2017; Zhang et al, 2017a,b). Previous studies have shown that epigenetic silencing of tumor suppressor genes results in the growth advantage of a clonal subpopulation of MDS. This epigenetic modification is reversible, and methyltransferase inhibitors, such as DAC, will reverse the situation and reactivate the silenced tumor suppressor genes (Itzykson and Fenaux, 2014).
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