Adenosine Kinase Expression Determines DNA Methylation in Cancer Cell Lines
- 9 April 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Pharmacology & Translational Science
- Vol. 4 (2), 680-686
- https://doi.org/10.1021/acsptsci.1c00008
Abstract
DNA methylation has a major role in cancer, and its inhibitors are used therapeutically. DNA methylation depends on methyl group flux through the transmethylation pathway, which forms adenosine. We hypothesized that an adenosine kinase isoform with nuclear expression (ADK-L) determines global DNA methylation in cancer cells. We quantified ADK-L expression (Western Blot) and global DNA methylation as percent 5-methyldeoxycytidine (5mdC, LC-MS/MS) in three cancer lines (HeLa, HepG2, and U373). ADK-L expression and global DNA methylation correlated positively with the highest levels in HeLa cells compared to U373 and HepG2 cells. To determine whether ADK increases global DNA methylation and to validate its potential therapeutics, we treated HeLa cells with potent ADK inhibitors MRS4203 and MRS4380 (IC50 88 and 140 nM, respectively). Both nucleosides, but not a structurally related poor ADK inhibitor, significantly reduced global DNA methylation in HeLa cells in a concentration-dependent manner. Thus, ADK-L is a potential target for the therapeutic manipulation of DNA methylation levels in cancer.Funding Information
- National Institute of Neurological Disorders and Stroke (NS065957, NS103740)
- National Institute of Diabetes and Digestive and Kidney Diseases (ZIADK31117)
This publication has 22 references indexed in Scilit:
- Deep sequencing reveals increased DNA methylation in chronic rat epilepsyActa Neuropathologica, 2013
- IDH1 mutation is sufficient to establish the glioma hypermethylator phenotypeNature, 2012
- Fused-core silica column ultra-performance liquid chromatography–ion trap tandem mass spectrometry for determination of global DNA methylation statusAnalytical Biochemistry, 2011
- Epigenetics in cancerCarcinogenesis: Integrative Cancer Research, 2009
- Quantification of regional DNA methylation by liquid chromatography/tandem mass spectrometryAnalytical Biochemistry, 2009
- Epigenetic therapy of cancer: past, present and futureNature Reviews Drug Discovery, 2006
- Specific Method for the Determination of Genomic DNA Methylation by Liquid Chromatography-Electrospray Ionization Tandem Mass SpectrometryAnalytical Chemistry, 2004
- [42] Preparation and enzymatic hydrolysis of DNA and RNA for mass spectrometryMethods in Enzymology, 1990
- Hypomethylation distinguishes genes of some human cancers from their normal counterpartsNature, 1983
- Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 4. Further modifications of the amino acid and base portions of S-adenosyl-L-homocysteineJournal of Medicinal Chemistry, 1976