SIRT1: Tumor promoter or tumor suppressor?
Introduction
Molecular genetic studies to elucidate the underlying mechanisms of aging process in model organisms have identified many individual genes involved in determining the fated life span [1]. The yeast SIR2 and its mammalian counterpart SIRT1, belonging to the family of type III histone/protein deacetylases [2], have brought much attention to investigators mainly due to its crucial roles in regulating a variety of molecular and cellular processes including anti-apoptosis [3], neuronal protection [4], calorie restriction [5], glucose metabolism [6], fat storage [7], insulin secretion [8], and cellular senescence [9]. A growing body of evidence thus suggests that the molecular functions of SIRT1 are highly pleiotropic.
Normal human cells have a finite number of population doublings due to a process termed replicative senescence when cultured in vitro [10]. Normal cells respond to the external stimuli such as ionizing radiation [11], oxidative stress [12], [13], DNA damage agents [14], and oncogene expression [15] by entering into cellular senescence, which is a state of irreversible growth arrest, regardless of their remaining proliferative potential. Cellular senescence is manifested by distinctive senescent phenotypes: enlarged and flattened morphology, multinucleated, and expression of beta-galactosidase. Cellular senescence is a potent tumor suppression mechanism [16]. It has been suggested that multicellular organisms have evolved apoptosis and cellular senescence to prevent cells from developing tumor [17].
SIRT1 inactivates transcriptional activity of p53 by deacetylating it [3], [9], [18]. Sustained overexpression of SIRT1 inhibits PML/p53-mediated cellular senescence [9], supporting the hypothesis that increased expression of SIRT1 is likely to extend replicative life span of normal human cells. In contrast, Mishishita et al. recently reported that replicative life span cannot be altered by overexpression of SIRT1 in normal cells. Interestingly, the complete removal of SIRT1 substantially extends replicative life span of mouse embryonic fibroblasts, revealing that the endogenous SIRT1 limits the replicative life span. However, Ota et al. [19] reported the conflicting evidence that knock-down of SIRT1 using small interfering RNA (siRNA) in both normal and malignant human cells caused senescence-like growth arrest. These findings suggest that the altered level of SIRT1 expression may lead to unexpected outcomes affecting molecular and cellular physiology of cells in cell-context specific manner (human versus mouse cells).
Cancer cell lines reveal higher endogenous level of SIRT1 expression compared with normal cells (Lim CS, unpublished data). It was shown that the use of SIRT1 inhibitor (Sirtinol) induces senescent-like growth arrest in the breast cancer cell line MCF-7 [19]. In addition, it was recently found that another SIRT1 inhibitor (nicotinamide) suppresses cell proliferation of MCF-7 cells (Lim CS et al., unpublished data). Taken together, there is every reason to think that SIRT1 is involved in a countless number of biological processes. In this report, my hypothesis is presented based on recent findings and observations of the published and unpublished data.
Section snippets
Mammalian SIRT1
Mammalian histone deacetylases are classified into three classes: type I, type II and type III [2]. Unlike the type I and II class members, type III family members (sirtuins 1 through 7) are nicotinamide adenine dinucleotide (NAD+)-dependent histone/protein deacetylases and are localized into both the nucleus and cytoplasm. SIRT1 is the most similar to yeast SIR2 and thus is presumed to be the ortholog of yeast SIR2. Thus far, a number of SIRT1 substrates and its interacting partners have been
SIRT1 and p53
The tumor suppressor p53 plays an important role in regulating cellular senescence [29]. p53 is a substrate for SIRT1, which inactivates p53 by deacetylating it [2], [3], [9], [18]. Recent findings showed that decrease in acetylation of p53 by sustained overexpression of SIRT1 [30] or increase in p53 acetylation by overexpressing SIRT1-H363Y (Lim et al., in press), which encodes a deacetylase-defective SIRT1, fails to reveal biological effects on replicative life span, and DNA damage response
SIRT1 and cancer
Higher level of SIRT1 expression in cancer cells compared with normal human cells has been observed (Lim CS, unpublished data), suggesting the possibility that SIRT1 is involved with tumorigenesis. In addition, Ota et al. [19] recently demonstrated that when SIRT1 function is interfered with its specific inhibitor sirtinol or small interfering RNA (siRNA) in MCF-7 cells, cells enter into a state of senescent-like growth arrest. It was further revealed that sirtinol causes impaired signaling of
Hypothesis
Although it is reasonable to speculate that SIRT1 contributes to tissue structure and function in normal cells and tissues, resulting in enhancing tissue integrity and longevity, it is my hypothesis that upregulated endogenous level of SIRT1, which is probably achieved by altered chromatin status, is accountable for promoting tumorigenesis as demonstrated in MCF-7 and that a functional p53 may not necessarily be required for SIRT1-mediated promotion of tumorigenesis. However, it is also
References (31)
- et al.
hSIR2 (SIRT1) functions as an NAD-dependent p53 deacetylase
Cell
(2001) The limited in vitro lifetime of human diploid cell strains
Exp Cell Res
(1965)- et al.
Human cell senescence as a DNA damage response
Mech Ageing Dev
(2005) - et al.
Irreversible cellular senescence induced by prolonged exposure to H2O2 involves DNA-damage-and-repair genes and telomere shortening
Int J Biochem Cell Biol
(2005) - et al.
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Cell
(1997) - et al.
dSIR2 and dHDAC6: two novel, inhibitor-resistant deacetylases in Drosophila melanogaster
Exp Cell Res
(2001) - et al.
Mammalian SIRT1 represses forkhead transcription factors
Cell
(2004) - et al.
FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1)
J Biol Chem
(2004) - et al.
SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1
J Biol Chem
(2005) - et al.
Mitochondria, oxidants, and aging
Cell
(2005)
Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression
Biochem Biophys Res Commun
Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress
Cell Metab
p53: 25 years after its discovery
Trends Pharmacol Sci
Sir2 links chromatin silencing, metabolism, and aging
Genes Dev
The Sir2 family of protein deacetylases
Annu Rev Biochem
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