MicroRNA Regulation of SIRT1

Abstract

SIRT1 is an NAD-dependent deacetylase that regulates stress response pathways. By deacetylating transcription factors and co-factors, SIRT1 modulates metabolism, inflammation, hypoxic responses, circadian rhythms, cell survival, and longevity. Since SIRT1 plays a key role in regulating pathways involved in cardiovascular diseases and metabolic diseases cancer, the regulation of SIRT1 has received intense scrutiny. The post-transcriptional regulation of SIRT1 is mediated by two classes of molecules, RNA-binding proteins (RBPs) and non-coding small RNAs. MicroRNAs (miRNAs) are short non-coding RNAs that regulate target gene expression in a post-transcriptional manner. More than 16 miRNAs modulate SIRT1 expression, including miR-34a. miR-34a induces colon cancer apoptosis through SIRT1, and miR-34a also promotes senescence in endothelial cells via SIRT1. This review describes the impact of miRNAs on SIRT1. The background of SIRT1 and miRNAs will be summarized, followed by the mechanism by which several key miRNAs alter SIRT1 levels, and how the RBP HuR regulates SIRT1. MicroRNA regulation of SIRT1 might affect a wide variety of pathways in humans, from metabolic diseases such as diabetes to cardiovascular diseases and cancer.

Keywords: HuR; RNA-binding proteins; SIRT1; miR-34a; microRNA.

Figure 1

The role of SIRT1 in vasculature. SIRT1 mediates important cellular processes in cardiovascular systems. Calorie restriction and resveratrol enhance SIRT1 expression and activity. SIRT1 modulates cellular responses in cardiovascular systems by regulating the activity of several transcription factors.

Figure 2

Regulation of SIRT1 by miRNAs. Schema shows that miRNAs regulate SIRT1 expression and function directly or through HuR. miR-22, miR-34, miR-143/145, miR-195, miR-199a, and miR-217 are expressed well in vascular tissues and control SIRT1 protein. SIRT1 is regulated by more than 15 miRNAs. miR-16, miR-125a, and miR-519 decrease HuR expression. In contrast, HuR controls the post-transcriptional regulation of miRNAs such as miR-122 and let-7. Moreover HuR binds to the 3′UTR of SIRT1 and changes SIRT1 mRNA stability.