Effects of Epigenetic Drugs (Vorinostat, Decitabine) on Metabolism-Related Pathway Factors in Leukemic Cells~!2010-02-03~!2010-03-25~!2010-05-17~!

Abstract

Novel tools for data-evaluation from gene-expression arrays allow analyses of biochemical pathways which may be influenced by treatment with epigenetic drugs which have originally been designed for re-activation of so-called tumour-suppressor genes that are known as key-molecules regulating differentiation or cell death in malignancy. Considering the fact that these processes are tightly associated with energy metabolism, this study evaluated the expression signature of prominently regulated pathways in the KG-1-leukemia cell line: Following a 3-day incubation, effects of pharmacologic concentrations from the histone-deacetylase inhibitor SAHA (suberoyl anilide hydroxamic acid, vorinostat) and the methylation-inhibitor desoxy-azacytidine (DAC) were comparatively analysed by transcriptional profiling (based on Affymetrix Human GeneChip Gene 1.0 ST microarrays) and quantitative real time PCR. Expression factors for pathways were calculated for comparative analyses. Epigenetic drugs SAHA and DAC had a downregulatory effect on metabolic pathway factors of carbohydrate metabolism and mitochondrial beta oxidation. Our data confirm SAHA-mediated downregulation of the histone deacetylase SIRT which regulates AKT-phosphatase. Associated pathways lead to regulation of numerous genes, including an upregulation of FOXO transcription factors. These regulatory networks are known for their crucial role in stem cell homeostasis and provide a mechanistic explanation for the fact that the number of SAHA-targeted genes (1392 up, 2651 down) exceeds the number of DAC-targeted genes (60 up, 15 down), besides known effects on cell-cycle-arrest and apoptosis induced by both drugs. Thus, our data underline that epigenetic mechanisms are tightly associated with malignancy-associated metabolic control at least at 3 levels, starting from (i) glucose-uptake over (ii) mitochondrial pathways to (iii) AKT-PTEN-FOXO- signalling. All of them are known to be regulated by caloric restriction. We propose that these interactions should be carefully considered in clinical application, providing the basis for optimization of drug-combinations and complex treatment strategies.