Inhibition of the mevalonate pathway affects epigenetic regulation in cancer cells

Area of Science:

• Biochemistry
• Molecular Biology
• Epigenetics

Background:

• The mevalonate pathway is crucial for post-translational modifications, including farnesylation, which regulates RAS downstream signaling.
• Aberrant signaling and epigenetic changes, such as DNA methyltransferase (DNMT1) stimulation and altered histone deacetylases (HDACs) and microRNAs, are observed in cancer cells.
• Mevalonate pathway inhibitors are emerging as potential anticancer agents, with evidence suggesting cross-talk between metabolic and epigenetic pathways.

Purpose of the Study:

• To investigate the epigenetic consequences of inhibiting the mevalonate pathway in cancer cells.
• To explore the impact of metabolic pathway inhibitors on gene expression, DNA methylation, and protein levels.
• To elucidate the connection between metabolic alterations and epigenetic modifications in cancer.

Main Methods:

• Transcriptomic, methylomic, and proteomic analyses were performed on cancer cell lines.
• Cells were treated with pharmacologic doses of mevalonate pathway inhibitors, including simvastatin and ibandronate.
• The study examined the effects on metabolic pathways, epigenetic regulators, and associated signaling networks.

Main Results:

• Pharmacologic doses of mevalonate pathway inhibitors induced significant epigenetic changes in cancer cells.
• Altered concentrations of NADPH were linked to metabolic pathway dysregulation and subsequent epigenetic consequences.
• The study revealed extensive cross-talk between mevalonate metabolism, vitamin D metabolism, and fatty acid synthesis, impacting epigenetic activity.

Conclusions:

• Metabolic therapies targeting the mevalonate pathway exert a far-reaching epigenetic impact on cancer cells.
• These findings provide a molecular explanation for the observed anticancer activity of statins and bisphosphonates.
• Understanding these metabolic-epigenetic interactions is crucial for developing novel cancer therapies.