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Glucose (20-40 mM) inhibition of E1-, E2-, and E3-induced SIRT1 expression in real-time PCR analysis. Dehydroepiandrostendione, androstenedione and testosterone (androgens), and estrone (E1), estradiol (E2), and estriol (E3) (estrogens) were added to HAECs at various doses, and time courses of SIRT1 expression were determined. Cell viability was estimated by counting the ratio of live cells using trypan blue exclusion.16 After each treatment, the numbers of total and live cells were calculated with trypan blue staining. These results suggest that DHEA, androstenedione, testosterone, E1, and E2 definitely activate SIRT1 expression in HAECs. Dehydroepiandrostendione, androstenedione, and testosterone remarkably produced a dose-dependent increase in SIRT1 expression in the range of 10 to 20 μg/ml.
SIRT4 overexpression reduces cell proliferation and transformation, and delays tumor development in a Tsc2−/− (tuberous sclerosis complex 2) mouse embryonic fibroblast xenograft model.154 Consistently, in another study, the loss of SIRT4 led to increased glutamine-dependent cell proliferation and stress-induced genomic instability, resulting in tumorigenic phenotypes.40 SIRT4 knockout mice spontaneously develop lung tumors.40 These studies indicate a crucial role of SIRT4 in linking glutamine metabolism with tumorigenesis. The mitochondrial sirtuin SIRT3 plays crucial roles in metabolism and oxidative stress response, and is considered as a mitochondrial tumor suppressor. SIRT1 promotes tumorigenesis and chemoresistance in HCC, and inhibition of SIRT1 consistently suppresses the proliferation of HCC cells in vitro or in vivo via the induction of cellular senescence or apoptosis.96–100 SIRT1 expression also positively correlates with c-MYC levels in HCC. Activating transcription factor 4 facilitates multidrug resistance in gastric cancer cells through direct binding to SIRT1 promoter and activating SIRT1 expression. SIRT1 inhibition via nicotinamide, sirtinol, short hairpin RNAs, or mutation of the 25 amino acid C-terminal SIRT1 activator sequence, results in a significant inhibition in the cell growth, viability, and chemoresistance.76–80 SIRT1 is highly expressed in advanced prostate cancer tissues and could promote prostate cancer cell invasion, migration, and metastasis through matrix metalloproteinase-2,81 EMT inducing transcription factor ZEB1,82 and cortactin.73,83 In the transgenic mouse model, SIRT1 expression promotes murine prostate carcinogenesis initiated by phosphatase and tensin homolog deficiency.84 SIRT4 is localized to mitochondria,21 and is a NAD+-dependent protein adenosine diphosphate (ADP)-ribosyl transferase, which catalyzes the transfer of ADP-ribosyl groups onto target proteins, such as GDH.16 SIRT4 regulates cellular metabolic functions like insulin secretion and fatty acid oxidation.16,38–40 Following genotoxic stress, SIRT4 has also exhibited an anti-apoptotic function by maintaining mitochondrial NAD+ levels together with SIRT3.41 SIRT4-depleted mice develop hyperinsulinemia and lung tumors.16,40 There are seven sirtuin genes, SIRT1-7, in mammals.10,11 Biochemically, they are a class of proteins that possess nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase (SIRT1, SIRT2, SIRT3, SIRT5, SIRT6, and SIRT7) and monoribosyltransferase (SIRT4 and SIRT6) activities.12–19 Recently, SIRT5 was shown to be a NAD+-dependent protein lysine demalonylase and desuccinylase.20 Sirtuin family members share a conserved NAD+-binding and catalytic core domain.
For example, SIRT6 is present in nucleoli during G1 but not in the S phase of the cell cycle, and slows down mitosis when overexpressed . Additionally, SIRT5 has the widest range of activity—apart from deacetylation, it can also cause demalonylation and desuccinylation. Sirtuins are class III deacetylases activated by NAD+ with different beneficial effects brought by the modification of the structure and function mainly of the DNA histone as well as many other proteins or formations of complexes with proteins. A systematic review and meta-analysis conducted by Dheresa et al. among women of reproductive age revealed an overall pooled random effect prevalence of gynecological morbidity at 22%. Sirtuins have a significant role in both the formation and the course of many gynecological diseases. The authors declare that the research was conducted in the absence of any financial or non-financial relationships that could be construed as a potential conflict of interest.
SIRT3 expression is higher in human lymph-node-positive breast cancer150 and oral squamous cell carcinoma (OSCC).151 Inhibition of SIRT3 in OSCC cells inhibits cell growth and anoikis (a form of programmed cell death) resistance, lowers tumor burden and incidence, and sensitizes OSCC cells to radiation and cisplatin treatments in vitro.151,152 The tumor suppressor p53 is deacetylated by SIRT3, and SIRT3 rescues p53-induced growth arrest in human bladder-tumor-derived EJ-p53 cells.153 SIRT3 deacetylates mitochondrial matrix protein IDH2 to protect cells from oxidative stress; but in cancer, IDH2 activation by SIRT3 may have a pro-survival effect on cancer cells. SIRT7 mRNA expression is increased in breast and thyroid cancer, compared to their normal counterparts.163 SIRT7 knockdown inhibits proliferation and induces apoptosis in U2OS cells.64 SIRT7 specifically deacetylates histone H3K18, which is necessary for maintaining tumor phenotypes of human cancer cells, including anchorage-independent growth and the escape from contact inhibition.18 Moreover, SIRT7 depletion markedly reduces the growth of human U251 cancer cell xenografts in mice.18 Very recently, both mRNA and protein levels of SIRT7 were shown to be increased in HCC, and knockdown of its expression efficiently suppressed tumor growth in vitro and in vivo.164 Here we present an extensive literature review of the roles of mammalian sirtuins, particularly SIRT1 as that is the most studied sirtuin, in human epithelial, neuronal, hematopoietic, and mesenchymal malignancies, covering breast, prostate, lung, thyroid, liver, colon, gastric, pancreatic, ovarian, and cervical cancers, tumors of the central nervous system, leukemia and lymphoma, and soft tissue sarcomas.
The sirtuin family has been found to be crucial for maintaining lipid and glucose homeostasis, and also for regulating insulin secretion and sensitivity, DNA repair pathways, neurogenesis, inflammation, and ageing. The differences in the degree of GDH acetylation were due to differences in the activity of SIRT3 in these cells, because this enzyme is a SIRT3 substrate. There were no differences in the group of younger women in the cumulus cells, but in the older group, the degree of acetylation of this enzyme was higher. An increase in the degree of GDH acetylation in granular cells was observed in young sick women compared to healthy women, and this increase was even higher in older women.
On the other hand, Tekin et al. observed a lack of association between other sirtuin—SIRT1—gene variants and endometrial cancer. SIRT7 was overexpressed in endometrial cancer cells when compared with normal endometrial cells, and, importantly, its downregulation inhibited the growth and invasiveness of endometrial cancer cells. The authors also revealed that knockdown of SIRT1 could downregulate the expression of SREBP1 and suppress cell proliferation. The authors documented that although p53 is an important target protein for SIRT1 action, the selective inhibitor of this deacetylase—EX527 significantly suppressed the proliferation and cisplatin resistance of three endometrial carcinoma cell lines regardless of the p53 mutation status.
Typical female cancers have a poor overall survival rate in patients, and late disease presentation and chemo-resistance are the main factors that lead to the mortality of such patients . Boyle et al. investigated the association between SIRT3 activity and insulin resistance and systemic oxidative stress as prominent features of pregnancies complicated by maternal obesity or gestational diabetes mellitus (GDM). SIRT1 is known to be susceptible to intracellular fluctuations in the NAD+/NADH ratio and may influence type 2 diabetes risk through its known epigenetic effects and β-cell apoptosis 115,116. Thus, dietary factors influence the NAD+/NADH ratio, and regulating SIRT1 activity may influence the development of these disturbances in fetuses . This effect could be used for therapeutic and preventive purposes for diseases such as metabolic syndrome, insulin resistance, and type 2 diabetes, by increasing the activity of SIRT1 and SIRT6 or increasing the level of NAD+ . As the abovementioned pathways are dysregulated in metabolic diseases, SIRT1 may be a potential therapeutic target for the control of hyperglycemia and hypercholesterolemia .
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