Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
J Immunol Res. 2017;2017:4302320. doi: 10.1155/2017/4302320. Epub 2017 Oct 16.
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.
骨髓增生异常综合征（MDS）中肿瘤抑制基因的表观遗传沉默可能赋予个别细胞克隆生长优势。目前，高风险 MDS 患者的推荐治疗方法是使用去甲基化药物地西他滨（DAC），该药物可以诱导沉默的肿瘤抑制基因重新表达。我们研究了 DAC 治疗对髓系 MDS 细胞系 SKM-1 的影响，并通过在 DAC 治疗前沉默其表达来研究潜在的肿瘤抑制转录因子 FOXO3A 的作用。我们发现 FOXO3A 在 SKM-1 细胞中处于失活、高磷酸化形式，但 DAC 既诱导 FOXO3A 表达，又通过降低其磷酸化水平使蛋白重新激活。此外，我们表明，这种 FOXO3A 激活负责 DAC 诱导 SKM-1 细胞向单核细胞分化，以及 SKM-1 细胞周期停滞、凋亡和自噬。综上所述，这些结果表明 FOXO3A 的重新激活可能有助于 DAC 在 MDS 中的治疗效果。
