Drug Design, Development and Therapy (Apr 2020)
Arsenic Disulfide Promoted Hypomethylation by Increasing DNA Methyltransferases Expression in Myelodysplastic Syndrome
Abstract
Qing-Bing Zhou,1 Zheng-Tang Liu,1 Hong-Zhi Wang,2 Xiao-Qing Guo,2 Yong-Gang Xu,2 Xiao-Mei Hu2 1China Academy of Chinese Medical Sciences, Institute of Geriatric Medicine, Xiyuan Hospital, Beijing, People’s Republic of China; 2Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Xiao-Mei HuDepartment of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Xiyuan Playground No. 1, Haidian District, Beijing 100091, People’s Republic of ChinaTel +86 186 1035 0593Email [email protected]: 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.Keywords: arsenic disulfide, myelodysplastic syndrome, hypermethylation, SKM-1 cell line
