Decitabine-Induced Changes in Human Myelodysplastic Syndrome Cell Line SKM-1 Are Mediated by FOXO3A Activation

The epigenetic silencing of tumor suppressor genes in myelodysplastic syndromes (mds) can potentially confer a growth advantage to individual cellular clones. currently,the recommended treatment for patients with high-risk mds is the methylation agent decitabine (dac),a drug that can induce the reexpression of silenced tumor suppressor genes. we investigated the effects of dac treatment on the myeloid mds cell line skm-1 and investigated the role of foxo3a,a potentially tumor-suppressive transcription factor,by silencing its expression prior to dac treatment. we found that foxo3a exists in an inactive,hyperphosphorylated form in skm-1 cells,but that dac both induces foxo3a expression and reactivates the protein by reducing its phosphorylation level. furthermore,we show that this foxo3a activation is responsible for the dac-induced differentiation of skm-1 cells into monocytes,as well as for skm-1 cell cycle arrest,apoptosis,and autophagy. collectively,these results suggest that foxo3a reactivation may contribute to the therapeutic effects of dac in mds. © 2017 wen zeng et al.