Arsenic Disulfide Promoted Hypomethylation by Increasing DNA Methyltransferases Expression in Myelodysplastic Syndrome
Arsenic Disulfide Promoted Hypomethylation by Increasing DNA Methyltransferases Expression in Myelodysplastic Syndrome
复制标题
二硫化砷通过增加骨髓增生异常综合征中 DNA 甲基转移酶的表达促进低甲基化
DOI：
10.2147/dddt.s239158
复制
发表时间：
2020-04
期刊：
影响因子：
--
通讯作者：
Hu Xiao-Mei
中科院分区：
文献类型：
--
作者：
Zhou Qing-Bing;Liu Zheng-Tang;Wang Hong-Zhi;Guo Xiao-Qing;Xu Yong-Gang;Hu Xiao-Mei
以往的研究表明，DNA甲基化在骨髓增生异常综合征（MDS）中起着重要作用。除了高甲基化，异常的低甲基化可导致癌症中致癌基因的转录激活，包括MDS。因此，MDS的治疗需要靶向DNA低甲基化的药物。本研究旨在探讨As2S2是否通过增加MDS中DNA甲基转移酶（dnmt）的表达来促进低甲基化。采用Human methylation 850K BeadChip检测10例MDS患者和3例健康供者骨髓的DNA甲基化。采用Q-PCR方法比较10例MDS患者和3例对照组DNMTs的mRNA表达情况。然后，用As2S2处理MDS细胞系SKM-1。处理2天后，应用Human Methylation 850K BeadChip分析细胞中基因甲基化状态的变化。采用Q-PCR和Western blot检测处理后SKM-1细胞中DNMTs mRNA和蛋白表达的变化。结果通过人甲基化850K检测，MDS患者与对照组相比共发现592个异常低甲基化基因。MDS患者DNMT1、DNMT3a和DNMT3b mRNA表达量明显低于健康人群。As2S2对SKM-1细胞的IC50值为4.97 μmol/L。与对照组相比，2 μmoL/L的As2S2处理导致SKM-1细胞中1718个位点的甲基化水平发生显著变化。与对照组相比，在1625个位点（94.58%）观察到高甲基化，对应975个基因。最后，2 μmoL/L和4 μmoL/L As2S2处理的SKM-1细胞中DNMT1、DNMT3a和DNMT3b的表达水平显著升高。结论As2S2作为一种新型的高甲基化药物在MDS中具有潜在的临床应用价值。
Background Previous studies have shown that DNA methylation plays a significant role in myelodysplastic syndrome (MDS). In addition to hypermethylation, aberrant hypomethylation can result in the transcriptional activation of oncogenes in cancer, including MDS. Therefore, drugs targeting DNA hypomethylation are needed for the treatment of MDS. This study aimed to investigate whether As2S2 promoted hypomethylation by increasing DNA methyltransferases (DNMTs) expression in MDS. Patients and Methods Ten bone marrow samples from MDS patients and 3 healthy donors were obtained for the examination of the DNA methylation with a Human Methylation 850K BeadChip. The mRNA expressions for the DNMTs in the ten MDS patients and 3 controls were compared by Q-PCR. Then, the MDS cell line SKM-1 was treated with As2S2. After 2 days of treatment, Human Methylation 850K BeadChip was applied to analyze the changes of gene methylation status in the cells. Q-PCR and Western blot were taken to test the changes of mRNA and protein expressions for DNMTs in SKM-1 cells after treatment. Results Five hundred ninety-two abnormally hypomethylated genes were found in MDS patients compared to those in controls by Human Methylation 850K. The mRNA expressions of DNMTs (DNMT1, DNMT3a and DNMT3b) in MDS patients were significantly lower than those in healthy individuals. The IC50 value of As2S2 for SKM-1 cells was 4.97 μmol/L.Treatment with As2S2 at 2 μmoL/L resulted in significant alterations in the methylation levels at 1718 sites in SKM-1 cells compared to those in the controls. Hypermethylation was observed in 1625 sites (94.58%), corresponding to 975 genes, compared to those in the controls. Finally, the expression levels of DNMTs (DNMT1, DNMT3a, and DNMT3b) significantly increased in SKM-1 cells treated with As2S2 at 2 μmoL/L and 4 μmoL/L. Conclusion These data show a potential clinical application of As2S2 as an innovative hypermethylation agent in MDS.
登录
查看更多内容
影响因子：
20.3
作者：
Vardiman, James W.;Thiele, Juergen;Bloomfield, Clara D.
通讯作者：
Bloomfield, Clara D.
影响因子：
9
作者：
Zorea J;Prasad M;Cohen L;Li N;Schefzik R;Ghosh S;Rotblat B;Brors B;Elkabets M
通讯作者：
Elkabets M
DOI：
10.2147/dddt.s34271
发表时间：
2012
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Cai Z;Bresell A;Steinberg MH;Silberg DG;Furlong ST
通讯作者：
Furlong ST
影响因子：
64.8
作者：
Wu, HJ;Chen, YP;Shang, YF
通讯作者：
Shang, YF
TEM 和内皮细胞之间的串扰通过 IGF1-IGF1R 信号在上皮性卵巢癌中调节血管生成和转移
影响因子：
8.8
作者：
Wang X;Zhu Q;Lin Y;Wu L;Wu X;Wang K;He Q;Xu C;Wan X;Wang X
通讯作者：
Wang X