title: 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.affiliation: Ludwig Boltzmann Cluster Oncology, Vienna, Austria. Electronic address: heidrun.karlic@meduniwien.ac.at.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Karlic
authors.affiliation: Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risks (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria.
authors.forename: Roman
authors.initials: R
authors.lastname: Thaler
authors.affiliation: Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gerner
authors.affiliation: Ludwig Boltzmann Cluster Oncology, Vienna, Austria; Signaling Networks Program, Division of Oncology, Department of Medicine I, Medical University Vienna, Vienna, Austria; Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Grunt
authors.affiliation: Signaling Networks Program, Division of Oncology, Department of Medicine I, Medical University Vienna, Vienna, Austria; Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria; Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Proestling
authors.affiliation: Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risks (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Haider
authors.affiliation: Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risks (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria.
authors.forename: Franz
authors.initials: F
authors.lastname: Varga
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis*; D004164:Diphosphonates / Q000494:pharmacology; D015536:Down-Regulation; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005227:Fatty Acids / Q000096:biosynthesis; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent / Q000378:metabolism; D000077557:Ibandronic Acid; D008148:Lovastatin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics; D009249:NADP / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology; D014807:Vitamin D / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D005227:Fatty Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D035683:MicroRNAs; D014807:Vitamin D; D009249:NADP; D008148:Lovastatin; D019821:Simvastatin; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D008798:Mevalonic Acid; D000077557:Ibandronic Acid
keywords: Mevalonate pathway; bisphosphonates; cancer metabolism; epigenetics; statins