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.

Physiologic Activity of Bisphosphonates – Recent Advances

“…VEGF and hypoxia inducible factor-α suppression [135] as well as inactivation of epidermal growth factor receptors [136]. There is also a report showing that bisphosphonates target the three most epigenetic cell levels, namely DNA methylation, histone deacetylation and microRNAs [137].…”

Cardioprotective cytokine interleukin‐33 is up‐regulated by statins in human cardiac tissue

“…We further investigated, which mechanisms are responsible for the increase of IL‐33. It was shown previously that the MVA pathway inhibitors simvastatin and ibandronate affect epigenetic regulation in cancer cells . We demonstrate here that the promoter region of IL‐33 comprises a more open chromatin structure in fluvastatin‐treated cardiac cells compared to untreated cells as analysed by promoter accessibility.…”

“…It was shown previously that the MVA pathway inhibitors simvastatin and ibandronate affect epigenetic regulation in cancer cells. 35 We demonstrate here that the promoter to a variety of proteins as post-translational modifications known as protein prenylation (protein farnesylation and geranylgeranylation). 56 We showed that GGPP abolished IL-33 expression induced by both statins and BPs, whereas only the effect of statins on IL-33 expression was reduced by MVA supplementation.…”

A potential role of hydrogen sulfide (H2S) in the regulation of the Ras-ERK signaling-dependent transcription of DNA methyltransferases

“…The first study showed that the treatment of breast cancer, prostate cancer and osteosarcoma cells with physiologically relevant concentrations of simvastatin induced down-regulation on DNMT1 expression at the mRNA and protein levels [62]. The second one showed that the lovastatin treatment of colorectal cancer cells reduced the DNMTs level and BMP gene expression as a result of the gene promoter demethylation [63].…”

“…Consequently, not a surprise that cholesterol metabolism affects epigenetics, particularly DNA methylation pattern. It turned out that several studies had proved the effect of mevalonate pathway inhibitors -statins -on DNMTs expression; however, they provide no evidence of a direct role of the Ras-ERK signaling [62][63][64].…”