SIRT6 Links Immune Response and Metabolism to Cancer

Review Article

Austin J Clin Pathol. 2014;1(1): 1004.

Zhenghong Lin*,Jinping Li

1Department of Pathology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611, USA. Tel: 312-5033023;

*Corresponding author: Zhenghong Lin, Department of Pathology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611, USA

Received: February 05, 2014; Accepted: March 10, 2014; Published: March 20, 2014

Abstract

NAD-dependent SIRTuin (SIRT) family deacetylases promote longevity in multiple organisms including yeast, worms, and flies. In mammalian genomes, there are seven members (SIRT1-SIRT7) in the SIRTuin family, with the function of SIRT1 being extensively studied in the past 10 years. Notably, another SIRTuin family member SIRT6, originally identified as mono-ADPribosyltransferase, has recently been drawing more and more attention since it can deacetylate histones and non-histone substrates, and has been emerging as critical regulators in diverse physiological and pathological scenarios including telomere maintenance, chromosome stability, DNA damage repair, glucose metabolism, mammalian aging, life span, and immunity. Dysregulation of SIRT6 leads to metabolic disorder such as type 2 diabetes and cancer. Here we review the recent advances of the function of SIRT6 in immune response, glucose metabolism, and tumorigenesis, and discuss its therapeutic potential in treating cancer.

Keywords: SIRT6; immune response; metabolism; cancer.

Introduction

NAD-dependent SIRTuin (SIRT) family deacetylases, the class III histone deacetylases (HDAC), can extend lifespan of several lower model organisms including yeast, worms, and flies [1]. Mammalian genomes encode seven SIRTuin proteins which share a highly conserved NAD+-binding and catalytic core domain, but have distinct flanking N- and C-terminal extensions [2,(Figure1)]. Except SIRT4, most mammalian SIRTuins had previously been demonstrated to bear a NAD+-dependent protein deacetylases activity. A variety of substrates have been identified for SIRT1 [3]. SIRT4 was originally thought to only have ADP-ribosyltransferase activity [4,5]. However, recently, deacetylation data from David Rauh and colleagues revealed that all seven human SIRTuins have deacetylation substrate candidates including SIRT4 [6].

The subcellular localizations of SIRTuins are quite different [7,(table 1)]. SIRT6 and SIRT7 are nuclear proteins [8,9,(table 1)]. SIRT1, while predominantly in nuclear, can shuttle between cytosol and nuclear in various tissues in response to different stimuli [10]. Whereas, SIRT2 is located mainly in cytoplasm. Different from the above, the other three members, SIRT3, SIRT4, and SIRT5, are primarily found in mitochondria which participate in a variety of metabolic events associated with the mitochondrial activity [11,12].

In the SIRTuin family, SIRT1 was the founding member and had drawn more attention in the past 10 years. Notably, SIRT6 has been increasingly identified as crucial regulators for a variety of physiological and pathological events, ranging from telomere maintenance, chromosome stability, DNA damage repair, mammalian aging, life span, immunity to glucose metabolism and cancer [8,13-20]. Here we highlight the recent progress of SIRT6 studies in immune response, glucose metabolism, and tumorigenesis and discuss the therapeutic potential of SIRT6 modulators in treating cancers.

The ADP-ribosytransferase activity of SIRT6

SIRT6 was reported to have both ADP-ribosytransferase activity [20,21] and deacetylase activity [14,22-24]. Mono-ADP-ribosylation, typically performed by separate families of intra-and extracellular enzymes in vertebrates, is thought to be a general mechanism of reversible protein modification within mammalian organisms [25]. Intracellular mammalian ADP-ribosyltransferases target substrates including molecular chaperone GRP78, translational elongation factor 2, and β-subunit of heterotrimeric G-proteins while extracellular ones generally function in immune system [21,25].