SIRT1 In Cancer Research Articles

Propofol inhibits colon cancer cell stemness and epithelial-mesenchymal transition by regulating SIRT1, Wnt/β-catenin and PI3K/AKT/mTOR signaling pathways

BackgroundPropofol is a common sedative-hypnotic drug used for general anesthesia. Recent studies have drawn attention to the antitumor effects of propofol, but the potential mechanism by which propofol suppresses colon cancer stemness and epithelial-mesenchymal transition (EMT) has not been fully elucidated.MethodsFor the in vitro experiments, we used propofol to treat LOVO and SW480 cells and Cell Counting Kit-8 (CCK-8) to detect proliferation. Self-renewal capacity, cell invasion and migration, flow cytometry analysis, qPCR and Western blotting were performed to detect the suppression of propofol to colon cancer cells and the underlying mechanism. Tumorigenicity and immunohistochemistry experiments were performed to confirm the role of propofol in vivo.ResultWe observed that propofol could suppressed stem cell-like characteristics and EMT-related behaviors, including self-renewal capacity, cell invasion and migration in colon cancer cells, and even suppressed tumorigenicity in vivo. Furthermore, investigations of the underlying mechanism revealed that propofol treatment downregulated SIRT1. SIRT1 overexpression or knockdown affected the stemness and EMT of colon cancer cells. Additionally, propofol reversed stemness and EMT in cells with overexpressing SIRT1 and subsequently inhibited the Wnt/β-catenin and PI3K/AKT/mTOR signaling pathways. Wnt/β-catenin pathway inhibitor and PI3K/AKT/mTOR pathway inhibitor blocked the propofol-induced reduction of sphere-formation and cell invasion-migration.ConclusionPropofol inhibits LOVO and SW480 cell stemness and EMT by regulating SIRT1 and the Wnt/β-catenin and PI3K/AKT/mTOR signaling pathways. Our findings indicate that propofol inhibits SIRT1 in cancer and is advantageous in colon cancer surgical treatment of patients with high SIRT1 expression.

Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases.

Sirtuin 1 (Sirt1) is a NAD+ dependent lysine deacetylase associated with the pathogenesis of various diseases including cancer. In many cancer types Sirt1 expression is increased and higher levels have been associated with metastasis and poor prognosis. However, it was also shown, that Sirt1 can have tumor suppressing properties and in some instances even a dual role for the same cancer type has been reported. Increased Sirt1 activity has been linked to extension of the life span of cells, respectively, organisms by promoting DNA repair processes and downregulation of tumor suppressor proteins. This may have the downside of enhancing tumor growth and metastasis. In mice embryonic fibroblasts depletion of Sirt1 was shown to decrease levels of the DNA damage sensor histone H2AX. Impairment of DNA repair mechanisms by Sirt1 can promote tumorigenesis but also lower chemoresistance toward DNA targeting therapies. Despite many biological studies, there is currently just one small molecule Sirt1 inhibitor in clinical trials. Selisistat (EX-527) reached phase III clinical trials for treatment of Huntington's Disease. New small molecule Sirt1 modulators are crucial for further investigation of the contradicting roles of Sirt1 in cancer. We tested a small library of commercially available compounds that were proposed by virtual screening and docking studies against Sirt1, 2 and 3. A thienopyrimidone featuring a phenyl thiocyanate moiety was found to selectively inhibit Sirt1 with an IC50 of 13 μM. Structural analogs lacking the thiocyanate function did not show inhibition of Sirt1 revealing this group as key for the selectivity and affinity toward Sirt1. Further analogs with higher solubility were identified through iterative docking studies and in vitro testing. The most active compounds (down to 5 μM IC50) were further studied in cells. The ratio of phosphorylated γH2AX to unmodified H2AX is lower when Sirt1 is depleted or inhibited. Our new Sirtuin 1 inhibiting thiocyanates (S1th) lead to similarly lowered γH2AX/H2AX ratios in mouse embryonic fibroblasts as Sirt1 knockout and treatment with the reference inhibitor EX-527. In addition to that we were able to show antiproliferative activity, inhibition of migration and colony forming as well as hyperacetylation of Sirt1 targets p53 and H3 by the S1th in cervical cancer cells (HeLa). These results reveal thiocyanates as a promising new class of selective Sirt1 inhibitors.

Modulating SIRT1 activity variously affects thymic lymphoma development in mice

SIRT1 is a protein deacetylase with a broad range of biological functions, many of which are known to be important in carcinogenesis, however much of the literature regarding the role of SIRT1 in cancer remains conflicting. In this study we assessed the effect of SIRT1 on the initiation and progression of thymic T cell lymphomas. We employed mouse strains in which SIRT1 activity was absent or could be reversibly modulated in conjunction with thymic lymphoma induction using either the N-nitroso-N-methylurea (NMU) carcinogenesis or the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) transgene. Decreased SIRT1 activity reduced the development of thymic lymphomas in the NMU-treated mice but was permissive for the formation of lung adenomas. Conversely, in the NPM-ALK transgenic mice, decreased SIRT1 activity had a modest promoting effect in the development of thymic lymphomas. The results of the work presented here add to the growing body of evidence that sirt1 is neither an outright oncogene nor a tumor suppressor. These opposing results in two models of the same disease suggest that the influence of sirt1 on carcinogenesis may lie in a role in tumor surveillance.

Distinct effects of SIRT1 in cancer and stromal cells on tumor promotion.

The lysyl deacetylase SIRT1 acts as a metabolic sensor in adjusting metabolic imbalance. To explore the role of SIRT1 in tumor-stroma interplay, we designed an in vivo tumor model using SIRT1-transgenic mice. B16F10 mouse melanoma grew more quickly in SIRT1-transgenic mice than in wild-type mice, whereas SIRT1-overexpressing one grew slowly in both mice. Of human tumors, SIRT1 expression in stromal fibroblasts was found to correlate with poor prognosis in ovarian cancer. B16F10 and human ovarian cancer (SKOV3 and SNU840) cells were more proliferative in co-culture with SIRT1-overexpressiong fibroblasts. In contrast, SIRT1 within cancer cells has a negative effect on cell proliferation. In conditioned media from SIRT1-overexpressing fibroblasts, matrix metalloproteinase-3 (MMP3) was identified in cytokine arrays to be secreted from fibroblasts SIRT1-dependently. Fibroblast-derived MMP3 stimulated cancer cell proliferation, and such a role of MMP3 was also demonstrated in cancer/fibroblast co-grafts. In conclusion, SIRT1 plays differential roles in cancer and stromal cells. SIRT1 in stromal cells promotes cancer growth by producing MMP3, whereas SIRT1 in cancer cells inhibits growth via an intracellular event. The present study provides a basis for setting new anticancer strategies targeting SIRT1.

Abstract LB-167: The role of Sirt1 in tumorigenesis

Abstract SIRT1 is a highly conserved NAD+-dependent protein deacetylase. Homologs of SIRT1 in lower model organisms are able to delay the aging process in response to nutrients. Although the SIRT1 protein deacetylase activities have been shown to regulate numerous transcription factors and co-factors (eg. PCG-1, p53), modulate cellular metabolism and promote cell survival and stress resistance, the role of SIRT1 in cancer metabolism, growth and survival is still highly controversial. Colorectal cancer is one of the most common malignancies in the world. However, there are few studies revealing the clinical relevance of the expression of SIRT1 and related markers in colorectal cancer with human tissue. Although recent studies have revealed that SIRT1 plays an important role in colorectal tumorigenesis, the exact role of SIRT1 in colorectal tumorigenesis is still controversial. Thus far, our data demonstrates that knocking out SIRT1 induces the acetylation of p53 and alters cellular metabolism. Deletion of SIRT1 in MEFs decreases glutamine uptake and increases cell death by trigging apoptosis pathways. As a result, SIRT1 KO MEFs fails to induce tumors in a xenograft model in nude mice. We have recently generated a mouse colon cancer model on SIRT1 intestine knockout mouse strains (SIRT1 iKO) and discovered that SIRT1 iKO mice display a reduced rate of tumorigenesis. To further confirm the role of SIRT1 on colon cancer, we propose to analyze the association of SIRT1 expression and the prognosis in colorectal cancer. Citation Format: Natalie Shunxiang Ren. The role of Sirt1 in tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-167. doi:10.1158/1538-7445.AM2015-LB-167

Abstract 33: Mammary gland-specific deletion of Sirt1 delays mammary tumor growth and progression

Abstract SIRT1, a type III HDAC, is involved in regulation of several cellular processes including longevity, inflammatory response, energy metabolism and stem cell maintenance. SIRT1 first emerged as a potential anti-aging factor but now it is implicated in a number of age-related diseases including carcinogenesis and also in cancer stem cell maintenance. SIRT1 is over-expressed and/or catalytically activated in a variety of human cancers, including breast cancer. Several lines of evidence suggest that SIRT1 plays an important role in the activation of oncogenic signalling in mammary epithelial cells and that inhibition of SIRT1 has a direct effect on tumor cell growth and apoptosis. Despite the fact that SIRT1 is mainly involved in the promotion of oncogenic signaling, it can also function as a tumor suppressor via deacetylation and subsequent destabilization of various oncoproteins such as c-Myc, β-catenin, NF-κB, and HIF1α. Further, SIRT1 activation by resveratrol protects BRCA1 mutation-associated breast cancer. Thus, the precise role of SIRT1 in cancer is still unclear and remains debatable; it is likely that SIRT1 function in cancer is tissue/context-dependent. Therefore, understanding the precise role of SIRT1 in mammary tumorigenesis is essential for the rational design of SIRT1-based novel therapeutic drugs to combat breast cancer. To understand the functional implications of SIRT1 in breast cancer, we generated mammary gland-specific Sirt1-conditional knockout mice. Sirt1 deletion is associated with reduced mammary gland outgrowth and terminal end bud development, leading to significant reduction in mammary stem and progenitor cell formation. This perturbed mammary gland outgrowth and reduced mammary stem and progenitor cell formation recovers either by puberty or by exogenous administration of estrogen, suggesting that Sirt1 plays a key role in mediating estrogen signalling in mammary gland. To assess the functional role of SIRT1 in mammary tumor growth and progression, we crossed Sirt1-knockout mice with MMTV-PyMT-Tg mice and C3(1)-SV40-Tg mice, two spontaneous murine mammary tumor models. Sirt1 deletion significantly reduces the development and growth of spontaneous mammary tumors in both mouse models. This phenomenon is associated with significant reduction in cancer stem cell (CSC) formation with dramatic reduction in CSC markers Slug and Sox2 expression. We also found that Sirt1 deletion reactivates tumor suppressor proteins p53 and Foxo3a. In conclusion, our study provides direct evidence that SIRT1 plays a key role in breast cancer growth and progression by maintaining cancer stem cells via stabilization of CSC drivers and inactivation of tumor suppressors in mammary gland. Thus, pharmacological agents targeted to disrupt SIRT1 function and signalling might have potential in breast cancer treatment. Citation Format: Sabarish Ramachandran, Rajneesh Pathania, Selvakumar Elangovan, Ganapathy Vadivel, Muthusamy Thangaraju. Mammary gland-specific deletion of Sirt1 delays mammary tumor growth and progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 33. doi:10.1158/1538-7445.AM2015-33

Multifaceted Modulation of SIRT1 in Cancer and Inflammation.

SIRT1 is a highly conserved NAD+-dependent protein deacetylase that is involved in diverse cellular processes. SIRT1 can deacetylate not only histones, but also a growing number of nonhistone substrates involved in multiple signaling pathways. Accumulating evidence has indicated that SIRT1 is a key regulator of life span extension, DNA damage, metabolism stress, inflammation, and cancer. In inflammation, SIRT1 deacetylates several transcription factors and regulates the immune cell responses. In cancer, recent discoveries revealed opposite effects of SIRT1 as an oncoprotein or a tumor suppressor under different conditions. In the tumor microenvironment, both infiltrated immune cells and cancer cells can be affected by SIRT1. Understanding the proper cancer-related functions of SIRT1 in both systems may provide potential evidence for SIRT1-based therapies. Here, we discuss the current understanding of SIRT1 in regulating immune responses and tumorigenesis.

The Role of SIRT1 in Cancer: The Saga Continues

This Commentary highlights the article by Di Sante etal, which presents data supporting the status of SIRT1 as a tumor suppressor in prostate cancer.

SIRT1 Is Downregulated in Gastric Cancer and Leads to G1-phase Arrest via NF-κB/Cyclin D1 Signaling

Sirtuin 1 (SIRT1) is a class III histone/protein deacetylase, and its activation status has been well documented to have physiologic benefits in human health. However, the function of SIRT1 in cancer remains controversial. Here, the expression and role of SIRT1 in gastric cancer is delineated. SIRT1 was present in all normal gastric mucosa specimens; however, it was only present in a portion of the matched gastric cancer tumor specimens. In SIRT1-positive tumors, both mRNA and protein levels were downregulated as compared with the corresponding nonneoplastic tissue. Ectopic expression of SIRT1 inhibited cell proliferation, diminished clonogenic potential, and induced a G1-phase cell-cycle arrest, the effects of which were not apparent when a catalytic-domain mutant form of SIRT1 was introduced, suggesting that SIRT1 functions in gastric cancer are dependent on its deacetylase activity. Further evidence was obtained from depletion of SIRT1. At the molecular level, SIRT1 inhibited the transcription of Cyclin D1 (CCND1), and inhibition of NF-κB in SIRT1-depleted cells rescued Cyclin D1 expression. Furthermore, inhibition of either NF-κB or Cyclin D1 in SIRT1-depleted cells reversed the inhibitory effects of SIRT1. The inhibitory role of SIRT1 was also verified in vivo using xenografts. This work characterizes SIRT1 status and demonstrates its inhibitory function in gastric cancer development, which involves NF-κB/Cyclin D1 signaling, offering a therapeutic role for SIRT1 activators. The inhibitory functions of SIRT1, which involve NF-κB/Cyclin D1 signaling, suggest the utility of SIRT1 activators in the prevention and therapy of gastric cancer.

Abstract 1068: Keratinocyte-specific deletion in mice reveals gene dose-dependent function of SIRT1 in tumorigenesis.

Abstract The protein deacetylase SIRT1, a mammalian counterpart of the yeast silent information regulator 2 (Sir2) and a proto member of the sirtuin family, regulates various pathways in metabolism, DNA repair, and cell survival. However, the role of SIRT1 in cancer is still under debate. Here we show that the role of SIRT1 in skin cancer development induced by the human skin carcinogen UVB radiation is dependent on its gene dose. Keratinocyte-specific heterozygous deletion of SIRT1 increases UVB-induced skin tumorigenesis, whereas homozygous deletion of SIRT1 decreases skin tumorigenesis. In mouse skin, SIRT1 is haploinsufficient for DNA repair and the expression of xeroderma pigmentosum C (XPC), a protein critical for repairing UVB-induced DNA damage. Similar to homozygous SIRT1 deletion, heterozygous SIRT1 deletion reduces the XPC protein levels and UVB-induced DNA damage repair. As compared with normal human skin, down-regulation of SIRT1 is in parallel with down-regulation of XPC in human cutaneous squamous cell carcinoma at both the protein and mRNA levels. In contrast, homozygous SIRT1 deletion in mouse skin augments p53 acetylation, and the expression of its transcriptional target Noxa, and sensitizes epidermis to UVB-induced apoptosis in vivo, while heterozygous SIRT1 deletion has no effect. Although mice with homozygous SIRT1 deletion do not develop tumors, these mice suffer severe sunburn. The gene dose-dependent function of SIRT1 in DNA repair and cell survival is consistent with its role in UVB-induced skin tumorigenesis and injury. Taken together, our results indicate that, depending on the SIRT1 levels, SIRT1 acts as a tumor suppressor and as an oncogene. Citation Format: Mei Ming, Keyoumars Soltani, Christopher R. Shea, Xiaoling Li, Yu-ying He. Keratinocyte-specific deletion in mice reveals gene dose-dependent function of SIRT1 in tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1068. doi:10.1158/1538-7445.AM2013-1068

The Roles of SIRT1 in Cancer

The sirtuin family has emerged as important regulators of diverse physiological and pathological events, including life-span extension, neurodegeneration, age-related disorders, obesity, heart disease, inflammation, and cancer. In mammals, there are 7 members (SIRT1-SIRT7) in the sirtuin family, with the function of SIRT1 being extensively studied in the past decade. SIRT1 can deacetylate histones and a number of nonhistone substrates, which are involved in multiple signaling pathways. Numerous studies have suggested that SIRT1 could act as either a tumor suppressor or tumor promoter depending on its targets in specific signaling pathways or in specific cancers. This review highlights the major pathways regulated by SIRT1 involved in tumorigenesis.

Analysis of 41 cancer cell lines reveals excessive allelic loss and novel mutations in the SIRT1 gene

SIRT1 is an evolutionarily conserved protein deacetylase that modulates stress response, cellular metabolism and aging in model organisms. While SIRT1 exerts beneficial effects in protecting against age-related diseases, the role of SIRT1 in cancer has been controversial. SIRT1 promotes cell survival by deacetylating, and thereby negatively regulating the activity of important tumor suppressors such as p53. In this regard, SIRT1 has been considered to be a potential oncogene, and SIRT1 inhibitors have been studied for possible anticancer therapeutic effects. In contrast, it has been shown that SIRT1 deficiency leads to increased genomic instability and tumorigenesis, and that overexpression of SIRT1 attenuates cancer formation in mice, suggesting it may also act as a tumor suppressor. Based on this evidence, SIRT1-activating molecules could act as candidate chemotherapeutic drugs. In order to gain insight into the role of SIRT1 in cancer, we performed a comprehensive resequencing analysis of the SIRT1 gene in 41 tumor cell lines and found an unusually excessive homozygosity, which was confirmed to be allelic loss by microsatellite analysis. Furthermore, we found two novel SIRT1 mutations (D739Y and R65_A72del) in addition to the known, rare non-synonymous variation resulting in I731V. In vitro assays using purified SIRT1 protein showed that these mutations do not alter SIRT1 deacetylase activity or telomerase activity, which was shown to be regulated by SIRT1. We conclude that allelic loss or mutations in the SIRT1 gene occur prevalently during tumorigenesis, supporting the assertion that SIRT1 may serve as a tumor suppressor.

SIRT1 promotes tumorigenesis of hepatocellular carcinoma through PI3K/PTEN/AKT signaling.

SIRT1 is the human orthologue of SIR2, a conserved NAD-dependent protein deacetylase that regulates longevity in yeast and in Caenorhabditis elegans. Overexpression of SIRT1 in cancer tissue, compared with normal tissue, has been demonstrated, suggesting that SIRT1 may act as a tumor promoter. The function of SIRT1 in liver cancer has not been elucidated. In the present study, SIRT1 re-expression or knockdown was induced in hepatoma cell lines and liver normal cell lines. Our study demonstrated that overexpression of SIRT1 promoted mitotic entry of liver cells, cell growth and proliferation and inhibited apoptosis. The apoptosis involved caspase-3 and caspase-7, and was related to the PTEN/PI3K/AKT signaling pathway. The results demonstrate that SIRT1 promotes tumorigenesis of hepatocellular carcinoma (HCC) through the PTEN/PI3K/AKT signaling pathway. SIRT1 may serve as a novel target for selective killing of cancer versus normal liver cells.

Abstract 179: MicroRNA-29c functions as a tumor suppressor by direct targeting endogenous SIRT1 in hepatocarcinogenesis

Abstract SIRT1 (Sirtuin 1) is the most well-known member of the class III histone deaceylase family which plays key roles in many cellular pathways by deacetylating or interacting with numerous non-histone proteins. Recent evidence has demonstrated that SIRT1 is up-regulated in a variety of human cancers and inhibition of SIRT1 expression or activity induces cancer cell growth retardation, cell cycle arrest and apoptosis. Although the functions of SIRT1 in cancer have been extensively studied, the underlying mechanisms of aberrant regulation of SIRT1 are not clearly understood. In the present study, we identified 5 microRNAs (miRNAs) that were significantly down-regulated in human hepatocellular carcinomas (HCCs) via large-scale miRNA expression analysis with computational prediction of miRNA targeting for SIRT1. Of these, it was found that miR-29c and miR-141 were directly able to suppress endogenous SIRT1 expression, but only miR-29c was able to recapitulate the effects of SIRT1 inactivation in HCC cells. In addition, the expression level of miR-29c was inversely correlated with SIRT1 protein expression levels in a subset of HCC tissues with their corresponding noncancerous tissue. The ectopic expressions of miR-29c in SNU-182 liver cancer cell lines suppressed cell growth and induced cell cycle arrest at G1-phase accompanied with the altered expressions of G1-related cellular components, such as CDK6, CDK2, cyclin D1, cyclin D3, phosphorylation of Rb and E2F1. Taken together, we suggest that loss or down-regulation of endogenous miR-29c causes aberrant overexpression of SIRT1 contributing oncogenic potential to the cells, and that a novel tumor suppression mechanism involving miR-29c may be amenable to epigenetic regulation in human HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 179. doi:1538-7445.AM2012-179

Sirtuin 1 (SIRT1): The Misunderstood HDAC

The sirtuin family of NAD-dependent histone deacetylases (HDACs) consists of seven mammalian proteins, SIRT1-7. Many of the sirtuin isoforms also deacetylate nonhistone substrates, such as p53 (SIRT1) and α-tubulin (SIRT2). The sirtuin literature focuses on pharmacological activators of SIRT1 (e.g., resveratrol, SRT1720), proposed as therapeutics for diabetes, neurodegeneration, inflammation, and others. However, many of the SIRT1 activator results may have been due to artifacts in the assay methodology (i.e., use of fluorescently tagged substrates). A biological role for SIRT1 in cancer has been given less scrutiny but is no less equivocal. Although proposed initially as an oncogene, we present herein compelling data suggesting that SIRT1 is indeed a context-specific tumor suppressor. For oncology, SIRT1 inhibitors (dual SIRT1/2) are indicated as potential therapeutics. A number of sirtuin inhibitors have been developed but with mixed results in cellular systems and animal models. It is unclear whether this has been due to poorly understood model systems, signalling redundancy, and/or inadequately potent and selective tool compounds. This review provides an overview of recent developments in the field of SIRT1 function. While focusing on oncology, it aims to shed light on new concepts of expanding the selectivity spectrum, including other sirtuins such as SIRT2.

SIRT1: recent lessons from mouse models

The family of protein deacetylases represented by yeast Sir2 has been the focus of intense investigation because of the longevity activity of Sir2 in yeast, worms and flies. Research in mammals has mainly focused on SIRT1, the closest homologue of Sir2. Emerging evidence from mouse models is yielding a sharper picture, in which SIRT1 is a potent protector from ageing-associated pathologies, such as diabetes, liver steatosis, cardiovascular disease, neurodegeneration and, importantly, various types of cancer.

The Critical Role of the Class III Histone Deacetylase SIRT1 in Cancer

Gene expression and deacetylase activity of the class III histone deacetylase SIRT1 are up-regulated in cancer cells due to oncogene overexpression or loss of function of tumor suppressor genes. SIRT1 induces histone deacetylation and methylation, promoter CpG island methylation, transcriptional repression, and deacetylation of tumor suppressor proteins. SIRT1 may play a critical role in tumor initiation, progression, and drug resistance by blocking senescence and apoptosis, and promoting cell growth and angiogenesis. SIRT1 inhibitors have shown promising anticancer effects in animal models of cancer. Further screening for more potent SIRT1 inhibitors may lead to compounds suitable for clinical trials in patients.

How does SIRT1 affect metabolism, senescence and cancer?

SIRT1 is a multifaceted, NAD(+)-dependent protein deacetylase that is involved in a wide variety of cellular processes from cancer to ageing. The function of SIRT1 in cancer is complex: SIRT1 has been shown to have oncogenic properties by downregulating p53 activity, but recent studies indicate that SIRT1 acts as a tumour suppressor in a mutated p53 background, raising intriguing questions regarding its mechanism of action. Here we discuss the current understanding of how SIRT1 functions in light of recent discoveries and propose that the net outcome of the seemingly opposite oncogenic and tumour-suppressive effects of SIRT1 depends on the status of p53.