SIRT3 and cancer: tumor promoter or suppressor?

Abstract

Sirtuins (SIRT1-7), the mammalian homologues of the Sir2 gene in yeast, have emerging roles in age-related diseases, such as cardiac hypertrophy, diabetes, obesity, and cancer. However, the role of several sirtuin family members, including SIRT1 and SIRT3, in cancer has been controversial. The aim of this review is to explore and discuss the seemingly dichotomous role of SIRT3 in cancer biology with particular emphasis on its potential role as a tumor promoter and tumor suppressor. This review will also discuss the potential role of SIRT3 as a novel therapeutic target to treat cancer.

Figure 1. Sirtuins subcellular localization

SIRT1 is predominantly located in the nucleus, and also in the cytosol. SIRT2 is localized in the cytosol. SIRT3, SIRT4, and SIRT5 are mitochondrial proteins, but SIRT3 may also be found in the nucleus and cytosol under different cellular events. SIRT6 and SIRT7 are localized in the nucleus and nucleolus, respectively.

Figure 2. SIRT3 diverse cellular functions. (Rt) The role of SIRT3 in survival, cell protection, and tumor promotion

Nicotinamide phosphoribosyltransferase (Nampt), a stress and nutrient-responsive gene, protects against genotoxic cell death via SIRT3 upregulation. Gene knockout (KO) of Ang II promotes longevity in mice either directly or indirectly through Nampt or SIRT3 upregulation. SIRT3 deacetylates Ku70, augmenting Ku70-Bax interaction, thus attenuating apoptosis and promoting cell survival in cardiomyocytes. In the heart, SIRT3 also prevents cardiac hypertrophy by attenuating reactive oxygen species (ROS), deacetylating cyclophilin-D, and activating the anti-hypertrophic LKB1-AMP kinase signaling pathway. Calorie restriction (CR) prevents aging and age-related diseases by augmenting SIRT3 levels and functions in the cell, at least in part, by deacetylating and activating superoxide dismutase 2 (SOD2), thus protecting the cell from ROS-induced cell death. In addition, ionizing radiation (IR) in normal cells may enhance SIRT3-deacetylated-MnSOD activation, therefore, again protecting the cell from ROS-induced cell death. Although it is still controversial, in neurons SIRT3 seems to protect cells from excitotoxic injury such as N-methyl-D-aspartate (NMDA)-induced neuronal death. SIRT3 deaceylates p53, attenuating p53-BAG2 complex stability (BAG2; BCL2-associated athanogene 2), thus decreasing apoptosis. Lymph node–positive breast cancer is associated with increased levels of SIRT3. SIRT3 is also overexpressed in oral cancer and in anoikis-resistant oral squamous cell carcinoma (OSCC) cells, thus promoting OSCC cell survival and preventing anoikis-mediated cell death.. (Lt) The role of SIRT3 in apoptosis, cell death, and tumor suppression. In colorectal carcinoma, Bcl-2 knockdown (KD) was associated with SIRT3 upregulation and apoptosis by deacetylating AceCS2 and switching on the JNK2 signaling pathway. In neurons, low potassium (LK)-induced apoptosis is mediated by SIRT3. In leukemia, the treatment with Kaempferol, a flavonoid that auto-oxidizes and generates ROS, induces apoptosis by SIRT3 and Bax upregulation, thus switching on caspase-3 cascades and apoptosis. SIRT3 is downregulated in human breast cancer cells compared to normal controls, and SIRT3^−/− mice developed mammary tumors over a 24-month period. In human colon carcinoma and osteosarcoma cells, SIRT3 also works as a tumor suppressor by suppressing ROS and HIF1-α. In HEK-293 cells, the transient receptor potential melastatin-related channel 2 (TRPM2), a nonselective cation channel induces cell death in response to oxidative stress via SIRT3. Unlike non-transformed cells, in some cancer cells, SIRT3 deacetylates cyclophilin-D, inducing the dissociation of hexokinase II/VDAC complex in the mitochondria, thus activating apoptosis.