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Depression is one of the most important and serious health problems in developing countries which affects millions of people. It is associated with the decrease of the quality of life as well as suicides and mortality. The disease may show recurrent episodes in some patients. Obviously, not all the patients with depression could be treated properly, because some individuals are drug-resistant and the options for the therapy are limited. Therefore, it is crucial to investigate new molecules and pathways that may have possible antidepressant activity. Sirtuin (SIRT), known as a class III histone deacetylase, which is regulated by nicotinamide adenine dinucleotide (NAD +), is one of these molecules. In the current study, we investigated the possible antidepressant-like effect of SIRT2 inhibitor AK-7. For this purpose, behavioral tests were performed in chronic AK-7-treated mice, and the expression levels of BDNF, NGF, NTF3, CREB, NTRK2, ERK1, ERK2, and GAP43 genes were evaluated by qRT-PCR analysis in brain tissues. Protein levels for BDNF, CREB1, and NTRK2 were determined by western blot. Our data showed that AK-7 significantly decreased immobility time and showed antidepressant-like effect. In addition, AK-7 treatment significantly increased mRNA levels of CREB and NTRK2 and protein levels of CREB1, BDNF, and NTRK2. Finally, our results suggest that SIRT2 and AK-7 may have a potential role in the cellular mechanisms of depression.

Sirtuin 2 (SIRT2), as a member of the sirtuin family, has representative features of evolutionarily highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase activity. In addition, SIRT2, as the only sirtuin protein colocalized with tubulin in the cytoplasm, has its own functions and characteristics. In recent years, studies have increasingly shown that SIRT2 can participate in the regulation of gene expression and regulate signal transduction in the metabolic pathway mainly through its post-translational modification of target genes; thus, SIRT2 has become a key centre in the metabolic pathway and participates in the pathological process of metabolic disorder-related diseases. In this paper, it is discussed that SIRT2 can regulate all aspects of gene expression, including epigenetic modification, replication, transcription and translation, and post-translational modification, which enables SIRT2 to participate in energy metabolism in life activities, and it is clarified that SIRT2 is involved in metabolic process-specific signal transduction mechanisms. Therefore, SIRT2 can be involved in metabolic disorder-related inflammation and oxidative stress, thereby triggering the occurrence of metabolic disorder-related diseases, such as neurodegenerative diseases, tumours, diabetes, and cardiovascular diseases. Currently, although the role of SIRT2 in some diseases is still controversial, given the multiple roles of SIRT2 in regulating physiological and pathological signal transduction, SIRT2 has become a key target for disease treatment. It is believed that with increasing research, the clinical application of SIRT2 will be promoted.

Sirtuins are protein deacylases regulating metabolism and stress responses and implicated in aging-related diseases. Modulators of the human sirtuins 1-7 are sought as chemical tools and potential therapeutics, for example, for treatment of cancer. We were able to show that 3-aryl-mercapto-succinylated- and 3-benzyl-mercapto-succinylated peptide derivatives yield selective Sirt5 inhibitors with low nM

Hepatitis B virus (HBV) is the leading cause of liver disease ranging from acute and chronic hepatitis to liver cirrhosis and hepatocellular carcinoma (HCC). Studies have revealed that HBV infection broadly reprogrammes the host cellular metabolic processes for viral pathogenesis. Previous reports have shown that glycolysis and gluconeogenesis are among the most deregulated pathways during HBV infection. We noted that despite being one of the rate-limiting enzymes of gluconeogenesis, the role and regulation of Fructose-1,6-bisphosphatase 1 (FBP1) during HBV infection is not much explored. In this study, we report FBP1 upregulation upon HBV infection and unravel a novel mechanism of epigenetic reprogramming of FBP1 by HBV via utilizing host factor Speckled 110 kDa (Sp110). Here, we identified acetylated lysine 18 of histone H3 (H3K18Ac) as a selective interactor of Sp110 Bromodomain. Furthermore, we found that Sp110 gets recruited on H3K18Ac-enriched FBP1 promoter, and facilitates recruitment of deacetylase Sirtuin 2 (SIRT2) on that site in the presence of HBV. SIRT2 in turn brings its interactor and transcriptional activator Hepatocyte nuclear factor 4-alpha to the promoter, which ultimately leads to a loss of DNA methylation near the cognate site. Interestingly, this Sp110 driven FBP1 regulation during infection was found to promote viral-borne HCC progression. Moreover, Sp110 can be used as a prognostic marker for the hepatitis-mediated HCC patients, where high Sp110 expression significantly lowered their survival. Thus, the epigenetic reader protein Sp110 has potential to be a therapeutic target to challenge HBV-induced HCCs.

Recent research on familial dysautonomia (FD) has focused on the development of therapeutics that facilitate the production of the correctly spliced, exon 20-containing, transcript in cells and individuals bearing the splice-altering, FD-causing mutation in the elongator acetyltransferase complex subunit I (ELP1) gene. We report here the ability of carnosol, a diterpene present in plant species of the Lamiaceae family, including rosemary, to enhance the cellular presence of the correctly spliced ELP1 transcript in FD patient-derived fibroblasts by upregulating transcription of the ELP1 gene and correcting the aberrant splicing of the ELP1 transcript. Carnosol treatment also elevates the level of the RNA binding motif protein 24 (RBM24) and RNA binding motif protein 38 (RBM38) proteins, two multifunctional RNA-binding proteins. Transfection-mediated expression of either of these RNA binding motif (RBMs) facilitates the inclusion of exon 20 sequence into the transcript generated from a minigene-bearing ELP1 genomic sequence containing the FD-causing mutation. Suppression of the carnosol-mediated induction of either of these RBMs, using targeting siRNAs, limited the carnosol-mediated inclusion of the ELP1 exon 20 sequence. Carnosol treatment of FD patient peripheral blood mononuclear cells facilitates the inclusion of exon 20 into the ELP1 transcript. The increased levels of the ELP1 and RBM38 transcripts and the alternative splicing of the sirtuin 2 (SIRT2) transcript, a sentinel for exon 20 inclusion in the FD-derived ELP1 transcript, are observed in RNA isolated from whole blood of healthy adults following the ingestion of carnosol-containing rosemary extract. These findings and the excellent safety profile of rosemary together justify an expedited clinical study of the impact of carnosol on the FD patient population.

Zinc-dependent histone deacetylases (HDACs) and sirtuins (SIRT) represent two different classes of enzymes which are responsible for deacylation of modified lysine side chains. The repertoire of acyl residues on lysine side chains identified

Background Acute kidney injury (AKI) is a public health problem with no specific therapies in the clinic and the underlying pathogenesis of AKI remains obscure. Bombesin receptor-activated protein (BRAP, C6ORF89 protein) was initially discovered as a ligand for a previously orphan G-protein-coupled receptor bombesin-like receptor-3. At present, accepted biological effects of BRAP include cell cycle progression, wound repair and the activation of histone deacetylases. However, its role in kidney disease is unknown. In this study we have investigated the role of BRAP and underlying mechanisms involved in cisplatin (CP)-induced AKI. Methods Here we used Bc004004 (homologous of C6ORF89 in mice) knockout mice and HK2 cells to investigate the effect of BRAP on AKI in vitro and in vivo. We analyzed ChIP-Seq and RNA-Seq data to search for the upstream regulators of BRAP and downstream mediators of BRAP action in AKI. Immunostaining, real-time polymerase chain reaction (PCR), co-immunoprecipitation, a dual-luciferase reporter assay and ChIP-PCR assay were applied to reveal the upstream and downstream regulation mechanism of BRAP during cisplatin-induced AKI. Results BRAP was downregulated in mice and human kidneys with AKI. Global Bc004004 deletion alleviated tubular cell apoptosis and necroptosis in CP-induced AKI mice, whereas local overexpression of BRAP in kidneys aggravated them. Pan-caspase inhibitor Z-VAD pretreatment attenuated CP-induced blood creatinine increase and kidney injury in wild-type mice but not in BRAP -/- mice. The activation of mixed lineage kinase like-domain was magnified by Z-VAD in CP-treated mice, especially in BRAP -/- mice. The cytoprotective effect of Z-VAD was more substantial than necrostatin-1 (Nec-1, an inhibitor of necroptosis) in CP-treated human kidney proximal tubular epithelial (HK2) cells. Furthermore, Nec-1 pretreatment reduced the CP-induced cell death in BRAP overexpression HK2 cells but did not work in cells with normal BRAP levels. We determined that CP treatment activated the nuclear factor-κB subunit P65 and inhibition of P65 increased the messenger RNA (mRNA) levels of BRAP in HK2 cells. The chromatin immunoprecipitation assay and dual-luciferase reporter gene assay verified P65 binding to the C6ORF89 promoter and reduced its mRNA expression upon CP treatment. Next we found that sirtuin 2 (SIRT2) was downregulated in CP-induced AKI and BRAP levels directly impacted the protein levels of SIRT2. Our findings further confirmed that BRAP regulates the SIRT2 protein levels by affecting SIRT2’s interactions with E3 ubiquitin ligase HRD1 and subsequent proteasomal degradation. Conclusions Our results demonstrated that BRAP played an important role in tubular cell apoptosis and necroptosis during CP-induced AKI. Safe and efficient BRAP inhibitors might be effective therapeutic options for AKI.

Lysine crotonylation (Kcr) is a newly identified protein translational modification and is involved in major biological processes including glycolysis, but its role in colorectal cancer (CRC) is unknown. Here, we found that the Kcr of α enolase (ENO1) was significantly elevated in human CRC tissues compared with the paratumoral tissues. CREB-binding protein (CBP) functioned as a crotonyltranferase of ENO1, and SIRT2 was involved in the decrotonylation of ENO1. Using quantitative mass spectrometry for crotonylomics analysis, we further found that K420 was the main Kcr site of ENO1 and ENO1 K420 Kcr promoted the growth, migration, and invasion of CRC cells in vitro by enhancing the activity of ENO1 and regulating the expression of tumor-associated genes. Our study reveals an important mechanism by which ENO1 regulates CRC through crotonylation.

Background: SIRT2 belongs to a class III of Histone Deacetylase (HDAC) and has crucial roles in neurodegeneration and malignancy. Objective: The objective of this study is to discover structurally novel natural-product-derived SIRT2 inhibitors. Methods: Structure-based pharmacophore modeling integrated with validated QSAR analysis was implemented to discover structurally novel SIRT2 inhibitors from the natural products database. The targeted QSAR model combined molecular descriptors with structure-based pharmacophore capable of explaining bioactivity variation of structurally diverse SIRT2 inhibitors. Manually built pharmacophore model, validated with receiver operating characteristic curve, and selected using the statistically optimum QSAR equation, was applied as a 3Dsearch query to mine AnalytiCon Discovery database of natural products. Results : Experimental in vitro testing of highest-ranked hits identified asperphenamate and salvianolic acid B as active SIRT2 inhibitors with IC50 values in low micromolar range. Conclusion: New chemical scaffolds of SIRT2 inhibitors have been identified that could serve as a starting point for lead-structure optimization.

Osteosarcomas (OS) are highly metastatic and usually lead to poor outcomes. Epithelial-mesenchymal transition (EMT) is reported to be a critical event in metastasis. SIRT2 exerts dual functions in many different tumors. However, the underlying molecular mechanisms of SIRT2 in osteosarcoma cell metastasis and the question of whether SIRT2 regulates EMT have not been fully explored. In this study, we confirmed that SIRT2 was highly-expressed in human osteosarcoma MG63 and Saos-2 cell lines. The viability, migration and invasion of osteosarcoma cells were inhibited by knockdown of SIRT2 and were enhanced by overexpression of SIRT2. Moreover, SIRT2 positively regulated EMT and upregulated the protein levels of the mesenchymal markers N-cadherin and Vimentin and the levels of MMP2 and MMP9. A xenograft mouse model showed that SIRT2 knockdown in osteosarcoma cells led to reduced tumor growth, decreased expression of mesenchymal markers and impaired lung and liver metastasis in vivo. Furthermore, we showed that SIRT2 interacted with and upregulated the protein level of the EMT-associated transcription factor Snail. SIRT2 inhibited Snail degradation via its deacetylase activity. Knockdown of Snail abrogated the promoting effects of SIRT2 on migration and invasion of osteosarcoma cells. In conclusion, SIRT2 plays a crucial role in osteosarcoma metastasis by inhibiting Snail degradation and may serve as a novel therapeutic target to manage osteosarcoma.

The regulatory relationship between silent information regulator 2 (SIRT2) and glucose 6‐phosphate dehydrogenase (G6PD) in clear cell renal cell carcinoma (ccRCC) is still unclear. The present study aimed to explore the function of SIRT2 and its regulatory effect on G6PD in ccRCC. The Cancer Genome Atlas data mining of SIRT2 was first analyzed. Quantitative real‐time PCR and western blot analyses were used to assess the mRNA and protein expression levels, respectively. Cell viability, colony formation, cell cycle, cell apoptosis, and TUNEL assays and EdU staining were used to investigate the roles of SIRT2 in ccRCC proliferation and apoptosis. The coimmunoprecipitation (Co‐IP) assay was used to analyze the association between SIRT2 and G6PD in ccRCC cells. Quantitative Co‐IP assay was used to detect the levels of G6PD ubiquitination and small ubiquitin‐related modifier 1 (SUMO1). An in vivo experiment was also carried out to confirm in vitro findings. The results indicated that SIRT2 promoted ccRCC proliferation and inhibited apoptosis by regulating cell cycle and apoptosis related proteins. Silent information regulator 2 interacted with G6PD, facilitated its activity through deacetylation, and increased its stability by reducing its ubiquitination and enhancing its SUMO1 modification. Silent information regulator 2 also promoted ccRCC tumor development in vivo. Taken together, the present study indicated that SIRT2 promoted ccRCC progression by increasing G6PD activity and stability, and it could be a potential new diagnostic and therapeutic target for ccRCC., The present study explores the function of silent information regulator 2 (SIRT2) and its regulatory effect of on glucose 6‐phosphate dehydrogenase in clear cell renal cell carcinoma (ccRCC). It aims to provide new molecular clues for targeted treatment of patients with ccRCC. The study supports an oncogenic role for SIRT2 in ccRCC and SIRT2 might be a potential therapeutic target for ccRCC.

Objectives Sirtuins comprise seven family elements (SIRT1-7) involved in various cell signalling pathways comprising cancer inhibition and tumorigenesis. The present study aims to evaluate SIRT2 and SIRT3 gene expression and potential redox reactions in patients with multiple myeloma (MM) at onset and its correlation with disease status, extent and presence of organ damage secondary to myeloma. Design & Methods Total RNA was extracted from 17 MM patients and 10 controls to assess gene expression using real-time PCR. The NAD+/NADH ratio as well as the levels of glutathione peroxidase (GPx) and hydrogen peroxide (HP) in peripheral blood mononuclear cells (PBMCs) were determined using established biochemical assays. Results SIRT2 and SIRT3 expression is reduced in MM patients compared to healthy controls. Correlational analysis demonstrated that SIRT2 reduction is associated with advanced clinical stage and with more advanced bone lesions than in the remaining patients. SIRT3 expression is correlated with lytic bone lesions. Biochemical analysis indicated an imbalance of oxidative stress biomarkers with low concentrations of the antioxidant enzyme GPx, low amounts of NAD + and higher concentrations of pro-oxidant enzyme HP in PBMCs of MM patients compared to controls. Moreover, MM patients with bone lesions had lower concentrations of NAD + and GPx in PBMCs than patients without signs of bone disease. In addition, MM patients had higher quantities of intracellular HP than controls. Conclusions Our results demonstrate that SIRT2 and SIRT3 are downregulated in MM and that lower concentrations correlate with an advanced stage of disease and redox imbalance. We conclude that SIRT2 and SIRT3 together with oxidative stress biomarkers, may be useful for improved risk stratification of MM patients.

Background/aim: Targeting the new and unique proteins is an important medical strategy for treating breast cancer. It is quite important to find out proteins that have a role in the development of cancer. Sirtuins (SIRT) are well related in different physiological activities and connected with cancer. We aimed to determine the effect of radiotherapy on SIRT1 and SIRT2, which have not been yet been clarified as a tumor suppressor or promoter. Materials and methods: Twenty-two women with nonmetastatic breast cancer enrolled in the study. Blood samples were taken before and after radiotherapy, soluble SIRT1 and SIRT2 levels were determined with ELISA kits. Results: There was no difference in SIRT1 levels before and after radiotherapy (p = 0.548). SIRT2 levels were significantly found to be decreased after radiotherapy (p = 0.042). There was a strong and positive correlation before radiotherapy (p < 0.001), and a moderate and positive correlation after radiotherapy (p = 0.007) between SIRT1 and SIRT2. Conclusion: These results suggest that SIRT2 may provide a new strategy for follow-up of breast cancer treatment. Additionally, by emphasizing the importance of SIRT2 in breast cancer, it opens ways to provide grounds for the development of the next generation of SIRT2-specific radiotracers. Finally, the most important thing, in fact, the positive correlation between SIRT1 and SIRT2 both before and after radiotherapy, appears to be clear evidence suggesting more oncogenic roles of sirtuins.

At present, cardiovascular disease is one of the important factors of human death, and there are many kinds of proteins involved. Sirtuins family proteins are involved in various physiological and pathological activities of the human body. Among them, there are more and more studies on the relationship between sirtuin2 (SIRT2) protein and cardiovascular diseases. SIRT2 can effectively inhibit pathological cardiac hypertrophy. The effect of SIRT2 on ischaemia‐reperfusion injury has different effects under different conditions. SIRT2 can reduce the level of reactive oxygen species (ROS), which may help to reduce the severity of diabetic cardiomyopathy. SIRT2 can affect a variety of cardiovascular diseases, energy metabolism and the ageing of cardiomyocytes, thereby affecting heart failure. SIRT2 also plays an important role in vascular disease. For endothelial cell damage used by oxidative stress, the role of SIRT2 is bidirectional, which is related to the degree of oxidative stress stimulation. When the degree of stimulation is small, SIRT2 plays a protective role, and when the degree of stimulation increases to a certain level, SIRT2 plays a negative role. In addition, SIRT2 is also involved in the remodelling of blood vessels and the repair of skin damage.

Background MicroRNA (miRNA) is a class of small-molecule RNA that can regulate gene expression at post-transcription level. It is involved in the genesis and development of multiple diseases. The aim of this paper was to explore the mechanisms of miR-339 in coronary heart disease (CHD). Methods In this study, we enrolled patients with CHD from Beijing Chaoyang Hospital and performed animal experiments on CHD rats. In vitro experiments, such as histopathologic assay, quantitative real-time PCR assay, luciferase reporter assay, western blotting assay, and immunofluorescence assay were carried out to characterize the contents and associations of miR-339, Nrf2, FOXO3, and Sirt2 in CHD samples and cells. In vivo model was also established on rats. Results In CHD rat, miR-339 was up-regulated compared with control group. The expression of miR-339 up-regulation increased oxidative stress in vitro model via suppression of Sirt2/Nrf2/FOXO3. However, down-regulation of miR-339 expression inhibited oxidative stress in vitro model via activation of Sirt2/Nrf2/FOXO3. The Sirt2 or Nrf2 inhibitor reduced the protective effect of miR-339 down-regulation on oxidative stress in vitro model. Conclusions Down-regulation miR-339 may be the new targets to treat CHD through Nrf2/FOXO3 targeting Sirt2, and miR-339 may be a potential biomarker of CHD.

BACKGROUND/AIM The purpose of this study was to examine the expression of estrogen receptor α (ERα) and β (ERβ), androgen receptor (AR), SIRT1, SIRT2 and SIRT3 in prostate cancer (PCa). MATERIALS AND METHODS From October 2010 to January 2015, 70 patients who had undergone radical prostatectomy following a PCa diagnosis were enrolled in our study. Normal prostate tissue (NPT) and prostate cancer tissues (PCAT) were separated, and the expression of each receptor in each tissue was analyzed with immunochemical staining. Univariate and multivariate analyses were performed to identify factors affecting the development of PCa. RESULTS ERβ and AR were highly expressed in PCAT compared with NPT (p

Epigenetic regulations essentially participate in the development of cardiomyocyte hypertrophy. PHD finger protein 19 (PHF19) is a polycomb protein that controls H3K36me3 and H3K27me3. However, the roles of PHF19 in cardiac hypertrophy remain unknown. Here in this work, we observed that PHF19 promoted cardiac hypertrophy via epigenetically targeting SIRT2. In angiotensin II (Ang II)-induced cardiomyocyte hypertrophy, adenovirus-mediated knockdown ofPhf19reduced the increase in cardiomyocyte size, repressed the expression of hypertrophic marker genesAnpandBnp, as well as inhibited protein synthesis. By contrast,Phf19overexpression promoted Ang II-induced cardiomyocyte hypertrophy in vitro. We also knocked downPhf19expression in mouse hearts in vivo. The results demonstrated thatPhf19knockdown reduced Ang II-induced decline in cardiac fraction shortening and ejection fraction.Phf19knockdown also inhibited Ang II-mediated increase in heart weight, reduced cardiomyocyte size, and repressed the expression of hypertrophic marker genes in mouse hearts. Further mechanism studies showed that PHF19 suppressed the expression of SIRT2, which contributed to the function of PHF19 during cardiomyocyte hypertrophy. PHF19 bound the promoter of SIRT2 and regulated the balance between H3K27me3 and H3K36me3 to repress the expression of SIRT2 in vitro and in vivo. In human hypertrophic hearts, the overexpression of PHF19 and downregulation of SIRT2 were observed. Of importance,PHF19expression was positively correlated with hypertrophic marker genesANPandBNPbut negatively correlated withSIRT2in human hypertrophic hearts. Therefore, our findings demonstrated that PHF19 promoted the development of cardiac hypertrophy via epigenetically regulating SIRT2.

Cold is a factor affecting health in humans and animals. The liver, a major metabolic center, is highly susceptible to ambient air temperature. Recent studies have shown that endoplasmic reticulum (ER) stress is associated with the liver, and regulates the occurrence and development of liver injury and autophagy. However, the mechanism underlying the relationship between cold exposure and ER stress in the liver is not well understood. In this study, we investigated the effect of ER stress on liver autophagy and its mechanism under cold exposure. AML12 cells were treated with Tg to construct an ER stress model, and the level of autophagy increased. To further explore the mechanism through which ER stress regulates autophagy, we knocked down SIRT2 with shRNA in Tg-treated AML12 cells. Knockdown of SIRT2 significantly increased ER stress and autophagy, increased FoxO1 acetylation, and promoted its entry into the nucleus. To further verify the results of in vitro experiments, we exposed mice to 4°C for 3 h per day for 3 weeks to exacerbate the burden on the liver after cold exposure. Cold exposure damaged the structure and function of the liver and promoted the inflammatory response. It also activated ER stress and promoted autophagy. In addition, cold exposure inhibited the expression of SIRT2, promoted FoxO1 acetylation, and enhanced the interaction with autophagy. Our findings indicated that cold exposure induces liver damage, ER stress, and autophagy through the SIRT2/FoxO1 pathway. These findings suggest that SIRT2 may be a potential target for regulating health under cold exposure.

SUMOylation is an important post-translational modification that participates in a variety of cellular physiological and pathological processes in eukaryotic cells. Sirt2, a NAD+-dependent deacetylase, usually exerts a tumor-suppressor function. However, the role of SUMOylation in cancer cells is not fully known. In this study, we found that SUMOylation can occur in the Sirt2 protein at both lysine 183 and lysine 340 sites. SUMOylation did not affect Sirt2 localization or stability but was involved in P38-mTORC2-AKT cellular signal transduction via direct deacetylation on a new substrate MAPK/P38. SUMOylation-deficient Sirt2 lost the capability of suppressing tumor processes and showed resistance to the Sirt2-specific inhibitor AK-7 in neuroblastoma cells. Here, we revealed the important function of Sirt2-SUMOylation, which is closely associated with cellular signal transduction and is essential for suppressing tumorigenesis in neuroblastoma.

Sirtuin isoform 2 (SIRT2) is an enzyme that catalyzes the removal of acyl groups from lysine residues. SIRT2's catalytic domain has a hydrophobic tunnel where its substrate acyl groups bind. Here, we report that the fluorescent probe 1-aminoanthracene (AMA) binds within SIRT2's hydrophobic tunnel in a substrate-dependent manner. AMA's interaction with SIRT2 was characterized by its enhanced fluorescence upon protein binding (>10-fold). AMA interacted weakly with SIRT2 alone in solution (Kd = 37 μM). However, when SIRT2 was equilibrated with a decanoylated peptide substrate, AMA's affinity for SIRT2 was enhanced ∼10-fold (Kd = 4 μM). The peptide's decanoyl chain and AMA co-occupied SIRT2's hydrophobic tunnel when bound to the protein. In contrast, binding of AMA to SIRT2 was competitive with a myristoylated substrate whose longer acyl chain occluded the entire tunnel. AMA competitively inhibited SIRT2 demyristoylase activity with an IC50 of 21 μM, which was significantly more potent than its inhibition of other deacylase activities. Finally, binding and structural analysis suggests that the AMA binding site in SIRT2's hydrophobic tunnel was structurally stabilized when SIRT2 interacted with a decanoylated or 4-oxononanoylated substrate, but AMA's binding site was less stable when SIRT2 was bound to an acetylated substrate. Our use of AMA to explore changes in SIRT2's hydrophobic tunnel that are induced by interactions with specific acylated substrates has implications for developing ligands that modulate SIRT2's substrate specificity.

Sirtuins are deacetylases dependent on nicotine adenine dinucleotide (NAD) and take an important role in metabolism and aging. In mammals, there are seven sirtuins (SlRTl-7), and only SIRT2 is predominantly localized in cytoplasm. Under hypoxic environments, metazoan organisms must maintain oxygen homeostasis to survive. Hypoxia conditions induce reduction the ratio of NAD+/NADH, and aberrant increases or decreases in cellular O2 concentration induced excessive reactive oxygen species generation. Here, we report that inhibition of SIRT2 stabilizes hypoxia-inducible factor 1α (HIF-1α) protein levels and enhances hypoxia-responsive element-containing gene expression. We also show that the SIRT2 inhibitor AGK2 induces VEGF and HO-1 gene expression and protects neuronal viability from oxidative stress. Our findings suggest that SIRT2 negatively regulates HIF-1α signaling, indicating that SIRT2 inhibition may be a useful treatment strategy following ischemic injury.

We have discovered the sirtuin‐rearranging ligands (SirReals) as a novel class of highly potent and selective inhibitors of the NAD+‐dependent lysine deacetylase sirtuin 2 (Sirt2). In previous studies, conjugation of a SirReal with a ligand for the E3 ubiquitin ligase cereblon to form a so‐called proteolysis‐targeting chimera (PROTAC) enabled small‐molecule‐induced degradation of Sirt2. Herein, we report the structure‐based development of a chloroalkylated SirReal that induces the degradation of Sirt2 mediated by Halo‐tagged E3 ubiquitin ligases. Using this orthogonal approach for Sirt2 degradation, we show that other E3 ligases than cereblon, such as the E3 ubiquitin ligase parkin, can also be harnessed for small‐molecule‐induced Sirt2 degradation, thereby emphasizing the great potential of parkin to be used as an E3 ligase for new PROTACs approaches. Thus, our study provides new insights into targeted protein degradation in general and Sirt2 degradation in particular., It's degrading: We report the structure‐based development of a chloroalkylated sirtuin rearranging ligand (SirReal) that induces Sirt2 degradation mediated by Halo‐tagged E3 ubiquitin ligases. Using this approach, we show that besides cereblon, other E3 ligases such as parkin, can be harnessed for small‐molecule‐induced Sirt2 degradation.

The aberrant expression of human sirtuin 2 (SIRT2) has been detected in various types of cancer; however, the biological roles, underlying mechanisms and clinical significance of SIRT2 dysregulation in human colorectal cancer (CRC) remain unclear. The results of this study demonstrate that compared with paired normal tissues, SIRT2 expression is significantly decreased in CRC tissues. SIRT2 loss has been correlated with clinicopathological characteristics, including distant metastasis, lymph node metastasis and American Joint Committee on Cancer (AJCC) stage; this loss serves as an independent factor that indicates a poor prognosis for patients with CRC. Further gain‐ and loss‐of‐function analyses have demonstrated that SIRT2 suppresses CRC cell proliferation and metastasis both in vivo and in vitro. Mechanistically, miR‐212‐5p was identified to directly target the SIRT2 3′‐untranslated region (3′‐UTR), leading to SIRT2 down‐regulation. The ectopic expression of SIRT2 reverses the effect of miR‐212‐5p overexpression on CRC cell colony formation, invasion, migration and proliferation. Clinically, an inverse correlation was found between miR‐212‐5p and SIRT2 expression. High miR‐212‐5p expression has been found to result in a poor prognosis and aggressive clinicopathological characteristics in patients with CRC. Taken together, these results suggest that SIRT2, targeted by miR‐212‐5p, acts as a tumour suppressor in CRC and that the miR‐212‐5p/SIRT2 axis is a promising prognostic factor and potential therapeutic target in CRC.

BACKGROUND Sirtuin2 (SIRT2), one of the members of the sirtuins family, has been proven to be a conserved protein. SIRT2 is reported to be associated with infection and inflammation, and its expression level in some cells such as mice brain can be reduced by the stimulation of lipopolysaccharide (LPS). We surmise that the expression levels of SIRT2 may be a warning signal of sepsis in the human body. METHODS A total of 38 intensive care units (ICU) patients with a diagnosis of sepsis/septic shock were recruited within 24 h of entry into the ICU. Serum procalcitonin (PCT), hypersensitive C-reactive protein (hs-CRP), and SIRT2 measurements were performed on admission, and on the second and fourth therapy days. The mRNA expression of SIRT2 was detected by real-time polymerase chain reaction (PCR). RESULTS We ascertained that the expression levels of SIRT2 mRNA in sepsis patients and septic shock patients were lower than those in the healthy volunteer control group (P

SIRT2 is a NAD+‐dependent deacetylase that deacetylates a diverse array of protein substrates and is involved in many cellular processes, including regulation of inflammation. However, its precise role in the inflammatory process has not completely been elucidated. Here, we identify heat‐shock protein 90α (Hsp90α) as novel substrate of SIRT2. Functional investigation suggests that Hsp90 is deacetylated by SIRT2, such that overexpression and knock‐down of SIRT2 altered the acetylation level of Hsp90. This subsequently resulted in disassociation of Hsp90 with glucocorticoid receptor (GR), and translocation of GR to the nucleus. This observation was further confirmed by glucocorticoid response element (GRE)‐driven reporter assay. Nuclear translocation of GR induced by SIRT2 overexpression repressed the expression of inflammatory cytokines, which were even more prominent under lipopolysaccharide (LPS) stimulation. Conversely, SIRT2 knock‐down resulted in the up‐regulation of cytokine expression. Mutation analysis indicated that deacetylation of Hsp90 at K294 is critical for SIRT2‐mediated regulation of cytokine expression. These data suggest that SIRT2 reduces the extent of LPS‐induced inflammation by suppressing the expression of inflammatory factors via SIRT2‐Hsp90‐GR axis.

Objectives: Improper activation of Wnt/β-catenin signaling has been implicated in human diseases. Beyond the well-studied glycogen synthase kinase 3β (GSK3β) and casein kinase 1 (CK1), other kinases affecting Wnt/β-catenin signaling remain to be defined. Methods:To identify the kinases that modulate Wnt/β-catenin signaling, we applied a kinase small interfering RNA (siRNA) library screen approach. Luciferase assays, immunoblotting, and real-time polymerase chain reaction (PCR) were performed to confirm the regulation of the Wnt/β-catenin signaling pathway by cyclin-dependent kinase 11 (CDK11) and to investigate the underlying mechanism. Confocal immunofluorescence, coimmunoprecipitation (co-IP), and scratch wound assays were used to demonstrate colocalization, detect protein interactions, and explore the function of CDK11. Results: CDK11 was found to be a significant candidate kinase participating in the negative control of Wnt/β-catenin signaling. Down-regulation of CDK11 led to the accumulation of Wnt/β-catenin signaling receptor complexes, in a manner dependent on intact adenomatosis polyposis coli (APC) protein. Further analysis showed that CDK11 modulation of Wnt/β-catenin signaling engaged the endolysosomal machinery, and CDK11 knockdown enhanced the colocalization of Wnt/β-catenin signaling receptor complexes with early endosomes and decreased colocalization with lysosomes. Mechanistically, CDK11 was found to function in Wnt/β-catenin signaling by regulating microtubule stability. Depletion of CDK11 down-regulated acetyl-α-tubulin. Moreover, co-IP assays demonstrated that CDK11 interacts with the α-tubulin deacetylase SIRT2, whereas SIRT2 down-regulation in CDK11-depleted cells reversed the accumulation of Wnt/β-catenin signaling receptor complexes. CDK11 was found to suppress cell migration through altered Wnt/β-catenin signaling. Conclusions: CDK11 is a negative modulator of Wnt/β-catenin signaling that stabilizes microtubules, thus resulting in the dysregulation of receptor complex trafficking from early endosomes to lysosomes.

Sirtuin-2 (Sirt2) is a member of the NAD (+)-dependent protein deacetylase family involved in neuroprotection, cellular metabolism, homeostasis, and stress responses after injury of the nervous system. So far, no data have been published describing the role of SIRT2 in motor functional recovery after damage. We found that SIRT2 expression and deacetylase activity were increased within motoneurons after axotomy. To shed light onto the biological relevance of this change, we combined in vitro and in vivo models with pharmacological and genetic ablation approaches. We found that SIRT2 KO (knockout) mice exhibited improved functional recovery after sciatic nerve crush. SIRT2 activity blockage, using AK7, increased neurite outgrowth and length in organotypic spinal cord cultures and human cell line models. SIRT2 blockage enhanced the acetyltransferase activity of p300, which in turn increased the levels of an acetylated form of p53 (Ac-p53 k373), histone 3 (Ac-H3K9), and expression of GAP43, a downstream marker of regeneration. Lastly, we verified that p300 acetyltransferase activity is essential for these effects. Our results suggest that bolstering an epigenetic shift that promotes SIRT2 inhibition can be an effective therapy to increase functional recovery after peripheral nerve injury. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00860-3) contains supplementary material, which is available to authorized users.

MORC family CW-type zinc finger 2 (MORC2) is an oncogenic chromatin-remodeling enzyme with an emerging role in DNA repair. Here, we report a novel function for MORC2 in cell-cycle checkpoint control through an acetylation-dependent mechanism. MORC2 is acetylated by the acetyltransferase NAT10 at lysine 767 (K767Ac) and this process is counteracted by the deacetylase SIRT2 under unperturbed conditions. DNA-damaging chemotherapeutic agents and ionizing radiation stimulate MORC2 K767Ac through enhancing the interaction between MORC2 and NAT10. Notably, acetylated MORC2 binds to histone H3 phosphorylation at threonine 11 (H3T11P) and is essential for DNA damage-induced reduction of H3T11P and transcriptional repression of its downstream target genes CDK1 and Cyclin B1, thus contributing to DNA damage-induced G2 checkpoint activation. Chemical inhibition or depletion of NAT10 or expression of an acetylation-defective MORC2 (K767R) forces cells to pass through G2 checkpoint, resulting in hypersensitivity to DNA-damaging agents. Moreover, MORC2 acetylation levels are associated with elevated NAT10 expression in clinical breast tumor samples. Together, these findings uncover a previously unrecognized role for MORC2 in regulating DNA damage-induced G2 checkpoint through NAT10-mediated acetylation and provide a potential therapeutic strategy to sensitize breast cancer cells to DNA-damaging chemotherapy and radiotherapy by targeting NAT10.

We would like to acknowledge and thank Pascale Cossart for her valuable insight and support throughout the project and for her contribution towards the acquisition of financial support. We also thank Michael G. Connor for his help in the quantification and analysis of microscopy data.; International audience; The NAD-dependent deacetylase Sirtuin-2 (SIRT2) functions in diverse cellular processes including the cell cycle, metabolism, and has important roles in tumorigenesis and bacterial infection. SIRT2 predominantly resides in the cytoplasm but can also function in the nucleus. Consequently, SIRT2 localisation and its interacting partners may greatly impact its function and need to be defined more clearly. In this study we used mass spectrometry to determine the interactomes of SIRT2 in whole cells and in specific cellular fractions; cytoplasm, nucleus and chromatin. Using this approach, we identified novel interacting partners of SIRT2. These included a number of proteins that function in nuclear import. We show that multiple importins interact with and contribute to the basal nuclear shuttling of SIRT2 and that one of these, IPO7 is required for SIRT2 mediated H3K18 deacetylation in response to bacterial infection. Furthermore, we reveal that the unstructured C-terminus of SIRT2 negatively regulates importin-binding and nuclear transport. This study demonstrates that SIRT2 is actively transported into the nucleus via a process regulated by its C-terminus and provides a resource of SIRT2 interacting partners.

Lysine fatty acylation in mammalian cells was discovered nearly three decades ago, yet the enzymes catalyzing it remain unknown. Unexpectedly, we find that human N-terminal glycine myristoyltransferases (NMT) 1 and 2 can efficiently myristoylate specific lysine residues. They modify ADP-ribosylation factor 6 (ARF6) on lysine 3 allowing it to remain on membranes during the GTPase cycle. We demonstrate that the NAD+-dependent deacylase SIRT2 removes the myristoyl group, and our evidence suggests that NMT prefers the GTP-bound while SIRT2 prefers the GDP-bound ARF6. This allows the lysine myrisotylation-demyristoylation cycle to couple to and promote the GTPase cycle of ARF6. Our study provides an explanation for the puzzling dissimilarity of ARF6 to other ARFs and suggests the existence of other substrates regulated by this previously unknown function of NMT. Furthermore, we identified a NMT/SIRT2-ARF6 regulatory axis, which may offer new ways to treat human diseases., Lysine fatty acylation is an important protein posttranslational modification but mammalian lysine fatty acyl transferases have remained unknown so far. Here the authors report that the human N-terminal glycine myristoyltransferases 1 and 2 catalyze the addition of myristoyl chains to specific lysine residues and show that they myristoylate ARF6 lysine 3, which explains the unusual membrane binding properties of ARF6.

Nicotinamide adenine dinucleotide (NAD

Sirtuin 2 (SIRT2), an NADIntegrating the published genomic data on NAFLD samples from humans and rodents available in the Gene Expression Omnibus, we found that SIRT2 was significantly down-regulated in livers from patients with advanced NAFLD and high-fat diet (HFD)-induced NAFLD mice. This study further revealed that SIRT2 was markedly decreased in obese (ob/ob) mice and in palmitate-treated HepG2 cells. Restoration of hepatic SIRT2 expression in ob/ob or HFD-fed mice largely alleviated insulin resistance, hepatic steatosis, and systematic inflammation, whereas SIRT2 liver-specific ablation exacerbated these metabolic dysfunctions in HFD-fed C57BL/6J mice. Mechanistically, SIRT2 stabilized the hepatocyte nuclear factor 4α (HNF4α) protein by binding to and deacetylating HNF4α on lysine 458. Furthermore, HNF4α was sufficient to mediate SIRT2 function, and SIRT2-HNF4α interaction was required for SIRT2 function both in vivo and in vitro.Collectively, the present study provided evidence that SIRT2 functions as a crucial negative regulator in NAFLD and related metabolic disorders and that targeting the SIRT2-HNF4α pathway may be a promising strategy for NAFLD treatment.

Persistent postsurgical neuropathic pain (PPSNP) can occur after intraoperative damage to somatosensory nerves, with a prevalence of 29-57% in breast cancer surgery. Proteomics is an active research field in neuropathic pain and the first results support its utility for establishing diagnoses or finding therapy strategies.57 women (30 non-PPSNP/27 PPSNP) who had experienced a surgeon-verified intercostobrachial nerve injury during breast cancer surgery, were examined for patterns in 74 serum proteomic markers that allowed discrimination between subgroups with or without PPSNP. Serum samples were obtained both before and after surgery.Unsupervised data analyses, including principal component analysis and self-organizing maps of artificial neurons, revealed patterns that supported a data structure consistent with pain-related subgroup (non-PPSPN vs. PPSNP) separation. Subsequent supervised machine learning-based analyses revealed 19 proteins (CD244, SIRT2, CCL28, CXCL9, CCL20, CCL3, IL.10RA, MCP.1, TRAIL, CCL25, IL10, uPA, CCL4, DNER, STAMPB, CCL23, CST5, CCL11, FGF.23) that were informative for subgroup separation. In cross-validated training and testing of six different machine-learned algorithms, subgroup assignment was significantly better than chance, whereas this was not possible when training the algorithms with randomly permuted data or with the protein markers not selected. In particular, sirtuin 2 emerged as a key protein, presenting both before and after breast cancer treatments in the PPSNP compared with the non-PPSNP subgroup.The identified proteins play important roles in immune processes such as cell migration, chemotaxis, and cytokine-signaling. They also have considerable overlap with currently known targets of approved or investigational drugs. Taken together, several lines of unsupervised and supervised analyses pointed to structures in serum proteomics data, obtained before and after breast cancer surgery, that relate to neuroinflammatory processes associated with the development of neuropathic pain after an intraoperative nerve lesion.

Breast carcinoma (BC) is the most commonly diagnosed type of cancer in women in the world. Although the advances in the treatment of BC patients are significant, numerous side effects, severe toxicity towards normal cells as well as the multidrug resistance (MDR) phenomenon restrict the effectiveness of the therapies used. Therefore, new active compounds which decrease the MDR, extend disease-free survival, thereby ameliorating the effectiveness of the current treatment regimens, are greatly needed. Histone deacetylase inhibitors (HDIs), including sirtuin inhibitors (SIRTi), are the epigenetic antitumor agents which induce a cytotoxic effect in different types of cancer cells, including BC cells. Currently, combined forms of therapy with two or even more chemotherapeutics are promising antineoplastic tools to obtain a better response to therapy and limit adverse effects. Thus, on the one hand, much more effective chemotherapeutics, e.g., sirtuin inhibitors (SIRTi), are in demand; on the other hand, combinations of accepted cytostatics are trialed. Thus, the aim of our research was to examine the combination effects of a renowned cytotoxic drug paclitaxel (PAX) and SIRT2 inhibitor AGK2 on the proliferation and viability of the T47D, MCF7, MDA-MB-231, MDA-MB-468, BT-549 and HCC1937 BC cells. Moreover, cell cycle arrest and apoptosis induction were explored. The type of pharmacological interactions between AGK2 and PAX in different molecular subtypes of BC cells was assessed using the advanced isobolographic method. Our findings demonstrated that the tested active agents singly inhibited viability and proliferation of BC cells as well as induced cell cycle arrest and apoptosis in the cell-dependent context. Additionally, AGK2 increased the antitumor effect of PAX in most BC cell lines. We observed that, depending on the BC cell lines, the combinations of tested drugs showed synergistic, additive or antagonistic pharmacological interaction. In conclusion, our studies demonstrated that the consolidated therapy with the use of AGK2 and PAX can be considered as a potential therapeutic regimen in the personalized cure of BC patients in the future.

Phenyl acetamide derivatives have a wide range of biological activities, so their research and development can be useful and effective for the design production of new drugs. In this project, quantitative structure-activity relationship (QSAR) was performed. For modeling two methods of multiple linear regression (MLR) and nonlinear regression of support vector machine (SVR) were used. In the MLR stage, the best model with the values of R

White matter damage (WMD) is the main cause of cerebral palsy and cognitive impairment in premature infants. Although caffeine has been shown to possess neuroprotective effects in neonatal rats with hypoxic-ischemic WMD, the mechanisms underlying these protective effects are unclear. Herein, proteins modulated by caffeine in neonatal rats with hypoxic-ischemic WMD were evaluated.We identified differential proteins and performed functional enrichment analyses between the Sham, hypoxic-ischemic WMD (HI), and HI+caffeine-treated WMD (Caffeine) groups. Confirmed the changes and effect of proteins in animal models and determined cognitive impairment via water maze experiments.In paraventricular tissue, 47 differential proteins were identified between the Sham, HI, and Caffeine groups. Functional enrichment analyses showed that these proteins were related to myelination and axon formation. In particular, the myelin basic protein (MBP), proteolipid protein, myelin-associated glycoprotein precursor, and sirtiun 2 (SIRT2) levels were reduced in the hypoxic-ischemic WMD group, and this effect could be prevented by caffeine. Caffeine alleviated the hypoxic-ischemic WMD-induced cognitive impairment and improved MBP, synaptophysin, and postsynaptic density protein 95 protein levels after hypoxic-ischemic WMD by preventing the HI-induced downregulation of SIRT2; these effects were subsequently attenuated by the SIRT2 inhibitor AK-7.Caffeine may have clinical applications in the management of prophylactic hypoxic-ischemic WMD; its effects may be mediated by proteins related to myelin development and synapse formation through SIRT2.

Objective. To investigate the roles and possible mechanisms of SIRT2 and KLF4 in the development and progression of myeloma. Methods. Rt-PCR was used to detect SIRT2 in myeloma samples from patients and myeloma cells, the expression level of KLF4 in myeloma cells, and the effect of downregulation of SIRT2 expression on KLF4 expression level. MTT assay and wound-healing assay were used to observe the proliferation and migration of U266cells transient transfected with Sirt2 inhibitors. Results. SIRT2 is highly expressed in myeloma, but KLF4 was down. Downregulation of SIRT2 expression stimulated the expression level of KLF4. Reduced SIRT2 activity results in the release of KLF4 expression, which inhibits the proliferation and migration of myeloma cells. Conclusion. SIRT2-KLF4 combination plays an important role in the occurrence and development of myeloma.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the production of renal ischemia/reperfusion (I/R). The current study is to elucidate a mechanism of SIRT2 tyrosine nitration to accelerate the cell apoptosis induced by peroxynitrite (ONOO‾), the most reactive and deleterious RNS type in renal ischemia/reperfusion (I/R) injury. Our results demonstrate that there is a significant enhancement of the 3-nitrotyrosine levels in renal tissues of Acute Kidney Injury (AKI) patients and rats that underwent renal I/R, and a positive correlation between the 3-nitrotyrosine level and renal function impairment, indicative of an accumulation of peroxynitrite. Notably, peroxynitrite-evoked nitration of SIRT2 destroyed its enzymatic activity and the capability to deacetylate FOXO3a, and enhanced expression of Bim and caspase3, facilitating renal cell apoptosis in renal ischemia/reperfusion and SIN-1(peroxynitrite donor) treatment in vitro, and these effects were reversed by FeTMPyP, a peroxynitrite decomposition scavenger. Importantly, we identified that the tyrosine 86 is responsible for SIRT2 nitration and inactivation using site-mutation assay and Mass Spectrography analysis. Altogether, these findings point to a novel protective mechanism that an inhibition of SIRT2 tyrosine nitration can be a promising strategy to prevent ischemic renal diseases involving AKI.

Purpose. Despite the discovery of many important molecules in diabetic nephropathy, there has been very limited progress in the management of diabetic kidney diseases and the design of new drugs. To fill this gap, the present study explored the expression of SIRT2 in high-glucose murine kidney foot cells and its impact on cell biological functions. Methods. Expression levels of SIRT2 in the MPC-5 of murine kidney foot cells after high and normal glucose treatment or in cells targeted with siRNA were detected using qRT-PCR. Cellular proliferation and programmed cell death were analyzed via the CCK8 assay and flow cell technique, separately. Levels of autophagy markers were measured by western blotting, and chloroquine treatment was applied to the cells to observe the effect of SIRT2 on cell proliferation and apoptosis after treatment. Results. The expression level of SIRT2 was remarkably upregulated in the high-GLU group in contrast to the low-GLU group. The cell proliferation and autophagy levels were significantly reduced, and apoptosis was remarkably reinforced in the high-GLU group in contrast to the normal GLU group. However, knocking down the expression level of SIRT2 caused an increase in cell proliferation and cell autophagy levels and significantly weakened apoptosis. Chloroquine influenced cell proliferation and apoptosis in cells targeted with SIRT2 siRNA. Conclusion. SIRT2 expression was upregulated in hyperglycaemic murine kidney foot cells, and knocking down the expression level of SIRT2 affected the biological function of the cells. We found that SIRT2 may modulate cell proliferation and apoptosis by regulating cell autophagy.

Aberrant IL-17A expression together with reduced IL-2 production by effector CD4(+) T cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Here, we report that Sirtuin 2 (SIRT2), a member of the family of NAD(+)-dependent histone deacetylases, suppresses IL-2 production by CD4(+) T cells while promoting their differentiation into Th17 cells. Mechanistically, we show that SIRT2 is responsible for the deacetylation of p70S6K, activation of the mTORC1/HIF-1α/RORγt pathway and induction of Th17-cell differentiation. Additionally, SIRT2 was shown to be responsible for the deacetylation of c-Jun and histones at the Il-2 gene, resulting in decreased IL-2 production. We found that the transcription factor inducible cAMP early repressor (ICER), which is overexpressed in T cells from people with SLE and lupus-prone mice, bound directly to the Sirt2 promoter and promoted its transcription. AK-7, a SIRT2 inhibitor, limited the ability of adoptively transferred antigen-specific CD4(+) T cells to cause autoimmune encephalomyelitis in mice and limited disease in lupus-prone MRL/lpr mice. Finally, CD4(+) T cells from SLE patients exhibited increased expression of SIRT2, and pharmacological inhibition of SIRT2 in primary CD4(+) T cells from patients with SLE attenuated the ability of these cells to differentiate into Th17 cells and promoted the generation of IL-2–producing T cells. Collectively, these results suggest that SIRT2-mediated deacetylation is essential in the aberrant expression of IL-17A and IL-2 and that SIRT2 may be a promising molecular target for new SLE therapies.

The sirtuin family of nicotinamide adenine dinucleotide-dependent deacetylase and ADP-ribosyl transferases plays key roles in aging, metabolism, stress response, and aging-related diseases. SIRT2 is a unique sirtuin that is expressed in the cytosol and is abundant in neuronal cells. Various microRNAs were recently reported to regulate SIRT2 expression via its 3′-untranslated region (UTR), and single nucleotide polymorphisms in the miRNA-binding sites of SIRT2 3′-UTR were identified in patients with neurodegenerative diseases. The present review highlights recent studies into SIRT2-mediated regulation of the stress response, posttranscriptional regulation of SIRT2 by microRNAs, and the implications of the SIRT2–miRNA axis in aging-related diseases.