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Cancer Genet. 2015 May;208(5):241-52. doi: 10.1016/j.cancergen.2015.03.008. Epub 2015 Mar 18.

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

Author information

1
Ludwig Boltzmann Cluster Oncology, Vienna, Austria. Electronic address: heidrun.karlic@meduniwien.ac.at.
2
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.
3
Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
4
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.
5
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.

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.

KEYWORDS:

Mevalonate pathway; bisphosphonates; cancer metabolism; epigenetics; statins

PMID:
25978957
PMCID:
PMC4503872
DOI:
10.1016/j.cancergen.2015.03.008
[Indexed for MEDLINE]
Free PMC Article

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