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DNA methyltransferase inhibitors (DNMT inhibitors) are administered for high-risk MDS, but their action mechanisms are not fully understood. Hence, we performed a genome-wide DNA methylation assay and focused on  cholesterol 25-hydroxylase  ( CH25H ) among the genes whose expression was up-regulated and whose promoter region was hypomethylated after decitabine (DAC) treatment  in vitro . CH25H catalyzes hydroxylation of cholesterol and produces 25-hydroxycholesterol (25-OHC). Although  CH25H  mRNA expression level was originally low in MDS/leukemia cell lines, exposure to DNMT inhibitors enhanced  CH25H  mRNA expression. The promoter region of  CH25H  was originally hypermethylated in HL-60 and MDS-L cells, but DAC treatment induced their hypomethylation together with increased  CH25H  mRNA expression, activation of  CH25H -oxysterol pathway, 25-OHC production and apoptotic cell death. We further confirmed that normal CD34-positive cells revealed hypomethylated status of the promoter region of  CH25H  gene.  CH25H -knockdown by transfection of shRNA lentiviral vector into the cell lines partially protected the cells from DAC-induced cell death. Exogenous addition of 25-OHC suppressed leukemic cell growth. The present study raises a possibility that DNMT inhibitors activate  CH25H -oxysterol pathway by their hypomethylating mechanism and induce leukemic cell death. Further investigations of the promoter analysis of  CH25H  gene and therapeutic effects of DNMT inhibitors on MDS/leukemia will be warranted.

Five-aza-2′-deoxycytidine-induced hypomethylation of cholesterol 25-hydroxylase gene is responsible for cell death of myelodysplasia/leukemia cells