Abstract
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.
Highlights
FOXO3A, known as forkhead in rhabdomyosarcomalike protein 1 (FKHRL1), is a transcription factor with important roles in embryonic development, differentiation, and tumorigenesis [1]
We investigated the effects of DAC on differentiation, apoptosis, cell cycle arrest, and autophagy using the myeloid myelodysplastic syndromes (MDS) tumor cell line SKM-1
While we observed no CD14 expression on the surface of SKM-1 cells, more than half of the cells expressed CD11b on their surface (59.71% ± 3.80%). This CD11b expression remained constant throughout DAC treatment, whereas CD14 expression gradually increased on exposure to DAC, with the proportion of CD14-positive cells reaching a maximum of 37.19% ± 9.44% (P < 0 05) after 6 days of treatment (Figures 1(a) and 1(b))
Summary
FOXO3A, known as forkhead in rhabdomyosarcomalike protein 1 (FKHRL1), is a transcription factor with important roles in embryonic development, differentiation, and tumorigenesis [1]. It is characterized by the presence of the distinctive forkhead DNA binding domain, a highly conserved winged helix motif, and regulates the transcription of genes involved in a variety of processes, including cell cycle regulation [2, 3], apoptosis [4, 5], DNA repair [6], and autophagy [7,8,9]. The reexpression and activation of FOXO3A in tumor cells reportedly have potential in antitumor treatment [20]
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