SIRTUINS 5º part

20.07.2018

Roles in cancer

The role of SIRT1 in tumor progression is controversial, as SIRT1 might have dual functions as an oncogene and tumor suppressor. The initial evidence that SIRT1 might function as an oncogene was the observation that it deacetylates lysine residue 383 of p53, thereby repressing its transcriptional activity (Luo et al., 2001; Vaziri et al., 2001). As p53 is a key tumor suppressor, its downregulation by SIRT1 could drive cells to tumorgenesis. In addition, two other tumor suppressors, deleted in bladder cancer 1 (DBC1) and hypermethylated in cancer 1 (HIC1) have been found to affect SIRT1. DBC1 binds to the N-terminus of SIRT1 and inhibits its enzymatic activity (Kim et al., 2008; Zhao et al., 2008), whereas HIC1 binds to the promoter region of the SIRT1 gene and represses its expression (Chen et al., 2005). As DBC1 and HIC1 are silenced in certain types of cancer cell, it has been speculated that they indirectly promote tumorgenesis – at least in part – through the resulting activation of SIRT1.

By contrast, several studies have shown that SIRT1 has also potential tumor suppressor effects. As discussed above, SIRT1 inactivates HIF1α through deacetylation and so protects against the growth of tumors and vascular formation – prerequisites for tumor progression (Lim et al., 2010). In addition, overexpression of SIRT1 in murine intestines reduces the incidence of cancer and growth in a mouse colon cancer model: SIRT1 was shown to deacetylate β-catenin and inhibit its accumulation in the nucleus, which lead to the hyperactivation of β-catenin and the formation of tumors (Firestein et al., 2008). Another study showed that the SIRT1 activator resveratrol also protects mice that are heterozygous for p53 from cancer (Boily et al., 2009; Oberdoerffer et al., 2008). Consistent with these results, it was shown that SIRT1 haploinsufficiency facilitates tumorigenesis in these mice by accelerating tumorigenesis (Wang et al., 2008). These data imply that SIRT1 functions as a tumor suppressor in vivo. However, the exact molecular effects of SIRT1 might vary in different tissues and/or cancer types.

Roles in neuronal functions and neurodegenerative diseases

Recent accumulating evidence shows that SIRT1 has also crucial roles in neuronal physiology and pathology. One of the most important neuronal functions of SIRT1 is its role in promoting feeding behavior during dietary limited conditions, including calorie restriction (CR) and fasting. Several studies suggest that SIRT1 expression is induced in hypothalamic pro-opiomelanocortin (POMC) expressing neurons, where it regulates various feeding behaviors (Cakir et al., 2009; Ramadori et al., 2010; Satoh et al., 2010). Correspondingly, mice in which SIRT1 was specifically knocked out in the brain lack the increase of adaptive physical activity in response to CR – a characteristic that is enhanced in mice overexpressing SIRT1 in their brains (Cohen et al., 2009; Satoh et al., 2010). SIRT1 also controls the central endocrine axes in the hypothalamus and pituitary gland. Mice in which SIRT1 was specifically knocked out in the brain have lower serum levels of growth hormones (Cohen et al., 2009). SIRT1 also positively regulates the secretion of thyroid-stimulating hormone (TSH) from the pituitary gland by deacetylating phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5Kγ), which has a crucial role in exoctytosis of TSH from pituitary cells (Akieda-Asai et al., 2010).

More recently, SIRT1 was found to modulate memory formation and synaptic plasticity (Michan et al., 2010; Gao et al., 2010). Here, SIRT1 promotes CREB expression through repression of the micro RNA 134 (miR134) and induces transcription of brain-derived neurotrophic factor (BDNF), which has crucial roles in normal cognitive function. Indeed, activation of SIRT1 in brain enhances, and its deletion impairs, memory formation and synaptic plasticity in mice (Gao et al., 2010).

Another recent study in mice indicates that SIRT1 is also implicated in Alzheimer's disease (AD) (Donmez et al., 2010). Using an AD mouse model, we have shown that overexpression of SIRT1 in the brain could prevent the formation of amyloid β (Aβ) plaques and rescue behavioral deficits. Here, SIRT1 directly activates retinoid acid receptor β (RARβ) through its deacetylation. RARβ activation, in turn, promotes transcription of a disintegrin and metallopeptidase 10 (ADAM10), which encodes for a component of α-secretase. The resulting increase in α-secretase activity leads to a reduced processing of toxic amyloid precursor protein (APP) (Donmez et al., 2010). In another AD mice model (mice that overexpress CDK5 p25), activation of SIRT1 by genetic or pharmacological means ameliorated neurodegeneration and memory decline (Kim et al., 2007). This study also uncovered a protective role for SIRT1 in amyotrophic lateral sclerosis (ALS) (Kim et al., 2007).

SIRT2

SIRT2 resides mainly in the cytoplasm but can also shuttle to the nucleus. SIRT2 can function as a α-tubulin deacetylase and was suggested to have a role in oligodendroglial differentiation (Li et al., 2007a; North et al., 2003). In the nucleus, SIRT2 acts as a H4K16 deacetylase and controls the cell cycle. MEFs, in which SIRT2 has been knocked out, accumulate H4K16 acetylation during mitosis and exhibit a delay in S-phase entry (Vaquero et al., 2006). SIRT2 also regulates adipocyte differentiation through FOXO1 deacetylation (Jing et al., 2007). Of particular note, a SIRT2-specific inhibitor can ameliorate α-synuclein-mediated toxicity in a Parkinson's disease model (Outeiro et al., 2007), but the mechanism underlying this effect is remains unknown. Further investigations are required to determine in greater depth the physiological and pathological functions of SIRT2.

Mitochondrial sirtuins SIRT3, SIRT4 and SIRT5

SIRT3, SIRT4 and SIRT5 are found in the mitochondrial matrix because they contain mitochondrion-targeting sequences in their N-termini (Haigis et al., 2006; Lombard et al., 2007; Nakagawa et al., 2009). SIRT3 is the best-characterized mitochondrial sirtuin. It interacts with acetyl-CoA synthetase 2 (AceCS2) and deacetylates lysine 642 in vitro and in vivo (Hallows et al., 2006; Schwer et al., 2006), thereby increasing its acetyl-CoA synthesis activity. Interestingly, the bacterial sirtuin CobB also regulates acetyl-CoA synthetase through its deacetylation, and cytoplasmic AceCS1 is regulated by SIRT1 in mammals (Hallows et al., 2006; Starai et al., 2002). Therefore, this mechanism of AceCS regulation appears to be evolutionary conserved. SIRT3 also deacetylates NDUFA9, a component of the OXPHOS complex I, which is involved in regulating cellular ATP levels (Ahn et al., 2008).

A recent study also revealed a new function of SIRT3 in fatty acid oxidation. Here, SIRT3 deacetylates long-chain acyl CoA dehydrogenase (LCAD) and upregulates its enzymatic activity during fasting (Hirschey et al., 2010). Moreover, SIRT3-knockout mice accumulate higher levels of fatty acid oxidation intermediates and have lower ATP levels during fasting (Hirschey et al., 2010).

In contrast to SIRT3, SIRT4 has only ADP-ribosylation but no deacetylation activity. It has been shown that SIRT4 can ADP-ribosylate glutamate dehydrogenase (GDH) and control insulin secretion in pancreatic β-cells in response to CR (Haigis et al., 2006). GDH is also deacetylated by SIRT3, but the physiological significance of this reaction is unknown (Lombard et al., 2007). SIRT4 also negatively regulates fatty acid oxidation and this effect is dependent on SIRT1 (Nasrin et al., 2010).

SIRT5 is also known to have a deacetylase activity. We have recently reported that SIRT5 has a role in the regulation of the urea cycle (Nakagawa et al., 2009). In this study, we uncovered that SIRT5 deacetylates and activates carbamoyl phosphate synthetase 1 (CPS1), an enzyme, which catalyzes the first and rate-limiting step of the urea cycle. SIRT5-knockout mice fail to upregulate CPS1 activity and are hyperammonemic during fasting, and similar effects were also observed with mice on a high protein diet or undergoing CR (Nakagawa et al., 2009). Conversely, SIRT5-overexpressing mice show increased CPS1 activity and urea production (Ogura et al., 2010). Thus, taken together, these findings support the idea that mitochondrial sirtuins directly control the activity of metabolic enzymes and have crucial roles in the metabolic adaptation to dietary conditions, such as calorie restriction and fasting.