Imatinib induces demethylation of miR-203 gene: an epigenetic mechanism of anti-tumor effect of imatinib

Tatsuki Shibuta; Emi Honda; Hiromichi Shiotsu; Yuka Tanaka; Shalini Vellasamy; Motoaki Shiratsuchi; Tsukuru Umemura

doi:10.1016/j.leukres.2013.07.019

Imatinib induces demethylation of miR-203 gene: an epigenetic mechanism of anti-tumor effect of imatinib

Leuk Res. 2013 Oct;37(10):1278-86. doi: 10.1016/j.leukres.2013.07.019. Epub 2013 Aug 13.

Authors

Tatsuki Shibuta¹, Emi Honda, Hiromichi Shiotsu, Yuka Tanaka, Shalini Vellasamy, Motoaki Shiratsuchi, Tsukuru Umemura

Affiliation

¹ Department of Health Sciences, Faculty of Medical Sciences, Graduate School of Medical Sciences, Kyushu University, Japan.

PMID: 23953880
DOI: 10.1016/j.leukres.2013.07.019

Abstract

MicroRNA (miRNA) is an important regulator of cellular proliferation, differentiation and death. Leukemia-specific signature of miRNAs suggests that epigenetic dysregulation of miRNAs is important for leukemogenesis. We focused on the role of DNA methylation of miR-203 which targets BCR-ABL1 mRNA. The microarray analysis showed that 48 miRNAs of CpG-rich 212 miRNAs were upregulated over 2-fold after imatinib treatment. Imatinib induced the demethylation of the miR-203 promoter region, resulting in low expression of targeted BCR-ABL1 gene, and loss of proliferation of leukemic cells. In conclusion, demethylation of miR-203 is one of the molecular mechanisms of imatinib-induced inhibition of BCR-ABL1-positive leukemic cells.

Keywords: CML; DNA methyltransferase; Methylation; MicroRNA; miR-203.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Benzamides / pharmacology*
Cell Line, Tumor
CpG Islands
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases / genetics
DNA (Cytosine-5-)-Methyltransferases / metabolism
DNA Methylation / drug effects*
DNA Methyltransferase 3B
Epigenesis, Genetic / drug effects*
Fusion Proteins, bcr-abl / genetics
Fusion Proteins, bcr-abl / metabolism
Gene Expression Profiling
Gene Expression Regulation, Leukemic / drug effects
Humans
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
MicroRNAs / genetics*
MicroRNAs / metabolism
Piperazines / pharmacology*
Promoter Regions, Genetic
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / pharmacology*
RNA, Messenger / genetics
RNA, Messenger / metabolism

Substances

Antineoplastic Agents
Benzamides
MIRN203 microRNA, human
MicroRNAs
Piperazines
Protein Kinase Inhibitors
Pyrimidines
RNA, Messenger
Imatinib Mesylate
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases
Fusion Proteins, bcr-abl