학술논문
Arsenic Disulfide Promoted Hypomethylation by Increasing DNA Methyltransferases Expression in Myelodysplastic Syndrome
Document Type
Academic Journal
Author
Source
Drug Design, Development and Therapy. May 31, 2020, p1641, 10 p.
Subject
Language
English
ISSN
1177-8881
Abstract
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 [As.sub.2][S.sub.2] 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 [As.sub.2][S.sub.2]. 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 [IC.sub.50] value of [As.sub.2][S.sub.2] for SKM-1 cells was 4.97 [micro]mol/LTreatment with [As.sub.2][S.sub.2] at 2 [micro]moL/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 [As.sub.2][S.sub.2] at 2 [micro]moL/L and 4 [micro]moL/L. Conclusion: These data show a potential clinical application of [As.sub.2][S.sub.2] as an innovative hypermethylation agent in MDS. Keywords: arsenic disulfide, myelodysplastic syndrome, hypermethylation, SKM-1 cell line
Plain Language Summary DNA aberrant hypomethylation plays an important role in the development of myelodysplastic syndrome (MDS). For example, Papaggeli PC demonstrated that the oncogenes c-myc and c-fos were often [...]
Plain Language Summary DNA aberrant hypomethylation plays an important role in the development of myelodysplastic syndrome (MDS). For example, Papaggeli PC demonstrated that the oncogenes c-myc and c-fos were often [...]