MicroRNA Regulation of SIRT1

Munekazu Yamakuchi

doi:10.3389/fphys.2012.00068

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.

Highlights

OF microRNAs MicroRNAs are non-coding ∼23 nt RNAs that control gene expression by suppressing translation or reducing stability of their target mRNAs (Bartel, 2004)
One or both single strands of mature miRNAs are incorporated into Argonaute (Ago2) in a miRNA–protein complex (RISC), which binds to the 3 untranslated region (3 UTR) of target mRNAs
We discovered that miR-34a regulates SIRT1, using a colon cancer cell line, HCT116 as a model system

Summary

Munekazu Yamakuchi *

Mice treated with SRT1720, a specific synthetic activator of SIRT1, are protected from diet-induced obesity and insulin resistance (Feige et al, 2008). Taken together, these in vivo results suggest that SIRT1 regulates mammalian metabolism. SIRT1 transgenic mice were protected from high-fat diet-induced obesity and liver steatosis (Banks et al, 2008; Pfluger et al, 2008). Prolongation of survival by caloric restriction increases SIRT1 activity (Bordone and Guarente, 2005). Loss of SIRT1 increases acetylation of FoxO1, a negative regulator of angiogenesis, thereby limiting angiogenic activity in endothelial cells (Potente et al, 2007).

BACKGROUND

Findings

Mouse ES cell