SIRT1: Tumor promoter or tumor suppressor?

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Summary

Over the past decade, an intensive research on the basic biology of aging has identified individual genes either directly or indirectly involved in regulating the aging process in various model organisms. This allows us to garner all the information available from studies of model organisms and to apply them to better understand aging and cancer in human. Among many genes thus far reported contributing to aging process, the yeast silent information regulator-2 (SIR2) and its homologues in other species, which belong to the family of type III histone and protein deacetylases, have been the subject of active discussion. The demonstrated roles of SIRT1, the mammalian counterpart of the yeast SIR2, reveal that SIRT1 regulates important cellular processes including anti-apoptosis, neuronal protection, cellular senescence, aging and longevity. Based on the observations that SIRT1 is upregulated in tumor cells, the hypothesis is that deregulation of SIRT1 expression may promote tumorigenesis by altering cellular signaling or by inducing modulation of chromatin remodeling leading to promotion of tumorigenesis. Further studies will shed new light on the underlying mechanisms of tumorigenesis mediated by SIRT1.

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

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