Semnan University of Medical Sciences

Research and Technology Vice Chancellor

Hassani, Saeed and Khaleghian, Ali and Ahmadian, Shahin and Alizadeh, Shaban and Alimoghaddam, Kamran and Ghavamzadeh, Ardeshir and Ghaffari, Seyed H. (2018) Redistribution of cell cycle by arsenic trioxide is associated with demethylation and expression changes of cell cycle related genes in acute promyelocytic leukemia cell line (NB4). Annals of Hematology, 97 (1). pp. 83-93. ISSN 0939-5555

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PML-RARα perturbs the normal epigenetic setting, which is essential to oncogenic transformation in acute promyelocytic leukemia (APL). Transcription induction and recruitment of DNA methyltransferases (DNMTs) by PML-RARα and subsequent hypermethylation are components of this perturbation. Arsenic trioxide (ATO), an important drug in APL therapy, concurrent with degradation of PML-RARα induces cell cycle change and apoptosis. How ATO causes cell cycle alteration has remained largely unexplained. Here, we investigated DNA methylation patterns of cell cycle regulatory genes promoters, the effects of ATO on the methylated genes and cell cycle distribution in an APL cell line, NB4. Analysis of promoter methylation status of 22 cell cycle related genes in NB4 revealed that CCND1, CCNE1, CCNF, CDKN1A, GADD45α, and RBL1 genes were methylated 60.7, 84.6, 58.6, 8.7, 33.4, and 73.7%, respectively, that after treatment with 2 μM ATO for 48 h, turn into 0.6, 13.8, 0.1, 6.6, 10.7, and 54.5% methylated. ATO significantly reduced the expression of DNMT1, 3A, and 3B. ATO induced the expression of CCND1, CCNE1, and GADD45α genes, suppressed the expression of CCNF and CDKN1A genes, which were consistent with decreased number of cells in G1 and S phases and increased number of cells in G2/M phase. In conclusion, demethylation and alteration in the expression level of the cell cycle related genes may be possible mechanisms in ATO-induced cell cycle arrest in APL cells. It may suggest that ATO by demethylation of CCND1 and CCNE1 and their transcriptional activation accelerates G1 and S transition into the G2/M cell cycle arrest. KEYWORDS: Acute promyelocytic leukemia; Arsenic trioxide; Cell cycle; Cyclin; Promoter methylation

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medical Sciences > School of Medicine
Depositing User: Mr Vahab Moshtaghi
Date Deposited: 05 May 2018 07:54
Last Modified: 23 May 2018 09:57

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