Zhang Zheng, Jia Yan, Xv Feng, Song Lu-Xi, Shi Lei, Guo Juan, Chang Chun-Kang
Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Front Genet. 2021 Jan 27;11:603956. doi: 10.3389/fgene.2020.603956. eCollection 2020.
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.
地西他滨（DAC）被认为是一种强效的全基因组DNA去甲基化药物，它能够诱导沉默的肿瘤抑制基因重新表达。目前对于肿瘤抑制基因FOXO1在骨髓增生异常综合征（MDS）中的功能了解甚少。为解决这一问题，该研究首先调查了DAC处理MDS细胞系后的差异表达基因（DEGs），然后通过在DAC处理前沉默其表达来探究FOXO1在MDS中的作用。结果显示，FOXO1在MDS-L细胞中以高磷酸化的无活性形式存在。DAC处理既能诱导FOXO1表达，又能使处于低磷酸化水平的该蛋白重新激活。此外，结果还表明这种FOXO1激活作用与DAC诱导的MDS-L细胞凋亡、细胞周期阻滞、抗原分化及免疫调节有关。我们还证明了DAC诱导的FOXO1激活可上调高危MDS标本中的抗肿瘤免疫反应。总体而言，这些结果表明DAC诱导FOXO1激活，这在抗MDS肿瘤中发挥着重要作用。
