Function And Mechanism Of Deacetylase SirT3 In Tumor Cell Metabolism

Sirtuins or Sir2 (Silent information regulator 2)-related enzymes have been defined as a family of nicotinamide-adenine dinucleotide(NAD+)-dependent histone deacetylase, which is highly conserved during evolution, and may link the metabolic rate of cells and oxidative stress to longevity. Numerous studies confirm that Sirtuins has played an important role in gene silencing, DNA damage and repair, mitosis regulation and anti-apoptosis.Human SirT3 is a mitochondrial member of Sirtuin family. Because of its deactylation of some vital none-histone proteins, SirT3 gets more and more attention these years. It is reported that SirT3 regulates global mitochondrial lysine acetylation. The identified substrates of SirT3 include AceCS2, glutamate dehydrogenase and succinate dehydrogenase, which are all central metabolic regulators in mitochondria. A small part of SirT3 also located in the nucleus, and deacetylates histion H4 and Ku70. That makes it can protect cells from stress-mediate cell death.SirT3 has been supposed as a mitochondrial tumor suppressor, affects cell ROS and energy metabolism level by regulates several mitochondrial proteins. In this study, we set up cell lines stably express Flag-SirT3 fusion protein to analyze the role of SirT3 in tumor cell metabolism. We used immunoprecipitation (IP) and mass spectrum, identified a series of SirT3-binding proteins.It is found out that SirT3 can bind and deacetylate Beclin-1 in the mitochondria, which is a key regulator of autophagy, and then promotes autophagy. And the binding is strengthened under stress. This evidence proves that SirT3 can affect on cell protein metabolism, and protects cells from stress condition through autophagy.In addition, we used several functional experiments to test SirT3 functions in tumor cells with the stable cell lines indicated. The results suggested that SirT3 may also promote mitosis, and then accelerates proliferation. Overexpression of SirT3 also down-regulates tumor cell adhesion and up-regulates cell migration. So we think that SirT3 may also promote tumor cell survival through some other kinds of metabolism, and leads to drug-resistant. Our study may provide a new way to develop SirT3-targeted tumor drugs, and a new approach of cancer therapy.