Inhibition of the mevalonate pathway affects epigenetic regulation in cancer cells.

Abstract

The mevalonate pathway provides metabolites for post-translational modifications such as farnesylation, which are critical for the activity of RAS downstream signaling. Subsequently occurring regulatory processes can induce an aberrant stimulation of DNA methyltransferase (DNMT1) as well as changes in histone deacetylases (HDACs) and microRNAs in many cancer cell lines. Inhibitors of the mevalonate pathway are increasingly recognized as anticancer drugs. Extensive evidence indicates an intense cross-talk between signaling pathways, which affect growth, differentiation, and apoptosis either directly or indirectly via epigenetic mechanisms. Herein, we show data obtained by novel transcriptomic and corresponding methylomic or proteomic analyses from cell lines treated with pharmacologic doses of respective inhibitors (i.e., simvastatin, ibandronate). Metabolic pathways and their epigenetic consequences appear to be affected by a changed concentration of NADPH. Moreover, since the mevalonate metabolism is part of a signaling network, including vitamin D metabolism or fatty acid synthesis, the epigenetic activity of associated pathways is also presented. This emphasizes the far-reaching epigenetic impact of metabolic therapies on cancer cells and provides some explanation for clinical observations, which indicate the anticancer activity of statins and bisphosphonates.

• Authors: Heidrun Karlic, Roman Thaler, Christopher Gerner, Thomas Grunt, Katharina Proestling, Florian Haider, Franz Varga
• Journal: Cancer genetics (Cancer Genet) Vol. 208 Issue 5 Pg. 241-52 (May 2015) ISSN: 2210-7762 [Print] United States
• PMID: 25978957 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Diphosphonates
• Fatty Acids
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• MicroRNAs
• Vitamin D
• NADP
• Lovastatin
• Simvastatin
• Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent
• DNA (Cytosine-5-)-Methyltransferase 1
• DNA (Cytosine-5-)-Methyltransferases
• DNMT1 protein, human
• Mevalonic Acid
• Ibandronic Acid

Topics

• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• DNA (Cytosine-5-)-Methyltransferase 1
• DNA (Cytosine-5-)-Methyltransferases (biosynthesis)
• Diphosphonates (pharmacology)
• Down-Regulation
• Epigenesis, Genetic (drug effects)
• Fatty Acids (biosynthesis)
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent (metabolism)
• Ibandronic Acid
• Lovastatin (pharmacology)
• Mevalonic Acid (antagonists & inhibitors, metabolism)
• MicroRNAs (genetics)
• NADP (metabolism)
• Neoplasms (genetics, metabolism)
• Protein Processing, Post-Translational (drug effects)
• Simvastatin (pharmacology)
• Vitamin D (metabolism)