Epigenetic effects of metformin: From molecular mechanisms to clinical implications

Abstract

There is a growing body of evidence that links epigenetic modifications to type 2 diabetes. Researchers have more recently investigated effects of commonly used medications, including those prescribed for diabetes, on epigenetic processes. This work reviews the influence of the widely used antidiabetic drug metformin on epigenomics, microRNA levels and subsequent gene expression, and potential clinical implications. Metformin may influence the activity of numerous epigenetic modifying enzymes, mostly by modulating the activation of AMP-activated protein kinase (AMPK). Activated AMPK can phosphorylate numerous substrates, including epigenetic enzymes such as histone acetyltransferases (HATs), class II histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), usually resulting in their inhibition; however, HAT1 activity may be increased. Metformin has also been reported to decrease expression of multiple histone methyltransferases, to increase the activity of the class III HDAC SIRT1 and to decrease the influence of DNMT inhibitors. There is evidence that these alterations influence the epigenome and gene expression, and may contribute to the antidiabetic properties of metformin and, potentially, may protect against cancer, cardiovascular disease, cognitive decline and aging. The expression levels of numerous microRNAs are also reportedly influenced by metformin treatment and may confer antidiabetic and anticancer activities. However, as the reported effects of metformin on epigenetic enzymes act to both increase and decrease histone acetylation, histone and DNA methylation, and gene expression, a significant degree of uncertainty exists concerning the overall effect of metformin on the epigenome, on gene expression, and on the subsequent effect on the health of metformin users.

Endothelial function and dysfunction: Impact of metformin

“…Emerging evidence has shown that metformin also has epigenetic functions, which has been reviewed elsewhere recently (Bridgeman, Ellison, Melton, Newsholme, & Mamotte, 2018).…”

Early‐onset aging and mitochondrial defects associated with loss of histone acetyltransferase 1 (Hat1)

“…Metformin functions by inducing AMPK activity. While AMPK down‐regulates many factors involved in epigenetic regulation, it phosphorylates and activates Hat1 (Bridgeman, Ellison, Melton, Newsholme, & Mamotte, ). A primary target of Hat1 acetylation, histone H4 lysine 12, has also been linked to aging.…”

Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy

“…As a consequence of the metforminmediated inhibition of mitochondrial electron transfer, metformin is able to activate a variety of AMPK-dependent and -independent signaling pathways through which it facilitates the inhibition of mTOR, inhibits the inflammatory pathway, and lastly disturbs inflammation, cellular survival, stress defense, protein synthesis, autophagy, and epigenetic reprogramming . [13][14][15][16][17][18][19][20] Downstream of these major biological outcomes, metformin might have the capacity to impact all the cancerimmune system interactions constituting the so-called "cancer immunogram". 21 Metformin might lead to systemically decreased levels of pro-inflammatory soluble inhibitors (e.g., serum levels of C-reactive protein and IL-6 [22][23][24] ), which are known to drive tumor-associated inflammation, impair T cell-mediated tumor control, and associate with poor outcomes in response to ICIs (1).…”