Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor
Gray, Steven G., Baird, Anne-Marie, O'Kelly, Fardod, Nikolaidis, Georgios, Almgren, Malin, Meunier, Armelle, Dockry, Éilis, Hollywood, Donal, Ekström, Tomas J., Perry, Antoinette S., & O'Byrne, Kenneth J. (2012) Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor. International Journal of Molecular Medicine, 30(6), pp. 1505-1511.
Gemcitabine is indicated in combination with cisplatin as first-line therapy for solid tumours including non-small cell lung cancer (NSCLC), bladder cancer and mesothelioma. Gemcitabine is an analogue of pyrimidine cytosine and functions as an anti-metabolite. Structurally, however, gemcitabine has similarities to 5-aza-2-deoxycytidine (decitabine/Dacogen®), a DNA methyltransferase inhibitor (DNMTi). NSCLC, mesothelioma and prostate cancer cell lines were treated with decitabine and gemcitabine. Reactivation of epigenetically silenced genes was examined by RT-PCR/qPCR. DNA methyltransferase activity in nuclear extracts and recombinant proteins was measured using a DNA methyltransferase assay, and alterations in DNA methylation status were examined using methylation-specific PCR (MS-PCR) and pyrosequencing. We observe a reactivation of several epigenetically silenced genes including GSTP1, IGFBP3 and RASSF1A. Gemcitabine functionally inhibited DNA methyltransferase activity in both nuclear extracts and recombinant proteins. Gemcitabine dramatically destabilised DNMT1 protein. However, DNA CpG methylation was for the most part unaffected by gemcitabine. In conclusion, gemcitabine both inhibits and destabilises DNA methyltransferases and reactivates epigenetically silenced genes having activity equivalent to decitabine at concentrations significantly lower than those achieved in the treatment of patients with solid tumours. This property may contribute to the anticancer activity of gemcitabine.
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|Item Type:||Journal Article|
|Keywords:||Cancer, DNA methyltransferase, DNMT inhibitor, Epigenetics, Gemcitabine, 5 aza 2' deoxycytidine, DNA methyltransferase 1, glutathione transferase P1, antineoplastic activity, article, cell strain, controlled study, CpG island, DNA methylation, drug structure, enzyme activity, gene silencing, priority journal, pyrosequencing, reverse transcription polymerase chain reaction, Antimetabolites, Antineoplastic, Azacitidine, Cell Line, Tumor, CpG Islands, Deoxycytidine, DNA (Cytosine-5-)-Methyltransferase, Enzyme Stability, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Histone Deacetylase 1, Humans, Promoter Regions, Genetic, Tumor Suppressor Proteins, Vascular Endothelial Growth Factor Receptor-1|
|Divisions:||Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
|Copyright Owner:||Copyright 2012 Spandidos Publications|
|Deposited On:||05 Dec 2013 00:57|
|Last Modified:||30 Jul 2014 02:54|
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