Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In addition to its action as a topoisomerase II poison, mitoxantrone is activated by formaldehyde to bind DNA, forming DNA-adducts specifically at 5'CpG and CpA sequences, with an enhancement of adducts at methylated CpG sites. The butyric acid prodrug, AN-9 (pivaloyloxymethyl butyrate), releases formaldehyde upon cellular hydrolysis and our previous studies have shown that mitoxantrone acts synergistically with AN-9 in cytotoxicity assays. In this paper, we investigated the impact of methylation levels in the cell on mitoxantrone-induced cytotoxicity using the colon cancer cell line HCT116 and its derived DNA methyltransferase (DNMT) 1 and DNMT 3a knockout (DKO8) cell line. We found that decreased methylation levels in the DNMT-null cells led to at least a 2-fold reduction in mitoxantrone-induced cytotoxicity. Next, we studied the impact of mitox-antrone alone, and in combination with AN-9, on hypermethylated genes and their mRNA expression in breast cancer cells. Using methylation-specific PCR and RT-PCR, we found that mitoxantrone treatment of breast cancer cell lines resulted in demethylation of the 14.3.3s, Cyclin D2 and ERa genes, followed by re-expression of their mRNA. The effect of mitoxantrone on re-expression of key genes involved in cell cycle regulation, and ensuing death of the cells may be an additional, previously undiscovered mechanism of action of mitoxantrone.
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PMID:Mitoxantrone mediates demethylation and reexpression of cyclin d2, estrogen receptor and 14.3.3sigma in breast cancer cells. 1287 62

We investigated the chemopreventive effects of naturally occurring compounds like butyric acid (BA), nicotinamide (NA) and calcium glucarate (CAG) individually or in combination in 7, 12-dimethylbenz [a] anthracene (DMBA) treated mouse skin at 4 and 16 weeks, the time before and after the tumor development. DMBA application did not show any skin tumors at 4 weeks but well defined tumors appeared at 16 weeks. BA, NA or CAG prevented the tumor development significantly but the protection was highly enhanced when all these compounds were given together. In order to see the molecular changes progressing with tumors, we showed the downregulation of tumor suppressor miR-203 at 16 weeks and upregulation of histone deacetylases (HDAC), DNA methyltransferase, promoter methylation of miR-203 at 4 or 16 weeks. Regulators of micro RNA biogenesis such as DICER1 and Ago2 were also deregulated by DMBA. Proto-oncogene c-myc and BMI1 were upregulated and tumor suppressor gene p16 was downregulated by DMBA as a function of time. Effects of BA, NA or CAG were more pronounced after 16 weeks as compared to 4 weeks in preventing the tumor development and altered gene expression. Concomitant administration of BA, NA and CAG tried to prevent these alterations more effectively than that of individual compound possibly by regulating miR-203 status through epigenetic or biogenetic modulations before and after the tumor development. Study provides a rationale for chemoprevention by combination of different compounds targeting miR-203.
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PMID:Modulation of miR-203 and its regulators as a function of time during the development of 7, 12 dimethylbenz [a] anthracene induced mouse skin tumors in presence or absence of the antitumor agents. 2479 73

First discovered on the natural killer (NK) cell, the cell surface inhibitory receptor sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7) is known for regulating many important biological activities. However, the detail regulatory mechanism for Siglec-7 expression in NK cells currently remains unclear. In this study, we aimed to investigate how cell surface Siglec-7 expression is regulated and found that, in both NK cell lines and peripheral NK cells, transcription was the main regulatory step. Furthermore, when NK-92MI and peripheral NK cells were treated with DNA methyltransferase (DNMT) inhibitor, the CpG island, with 9 CpG sites, in 5' Siglec-7 promoter became noticeably hypomethylated, and Siglec-7 expression increased in both RNA transcript and surface protein. Within this CpG island, we identified both CpG 8 and CpG 9 as two key regulators responsible for Siglec-7 expression. Additionally, by using histone deacetylases (HDAC) inhibitor, butyric acid, we showed that Siglec-7 expression was also subjected to the histone modification. And a combined treatment with both 5-azacytidine and butyric acid showed an additive effect on Siglec-7 transcript expression in peripheral NK cells.
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PMID:DNA methylation-mediated Siglec-7 regulation in natural killer cells via two 5' promoter CpG sites. 3202 25