Figure 4 - uploaded by Scarlett Acklin
Content may be subject to copyright.
NAD + -mediated enhancement of NER efficiency requires SIRT2 and is independent of SIRT1. (A) Western blot showing the activation effects of 5 nM NAD + on SIRT2 expression and deacetylase activity (n = 3), which is indicated by the level of α-tubulin AcK40. (B) NAD + administration enhanced NER efficiencies in a SIRT2-dependent manner in neuronally differentiated 50B11 cells (n = 3). (C) Western blot showing the effects of administration of 5 nM NAD + on SIRT1 expression and deacetylase activity in 50B11 cells in which SIRT1 expression is modified using siRNA against SIRT1 (n = 3). Deacetylase activity is indicated by acetylation of p53 at K373/K382 (AcK373.382). (D) SIRT1 expression and activity did not affect NAD + -mediated enhancement of NER efficiencies in 50B11 cells (n = 3). Statistical significance was assessed using 2-way ANOVA with Bonferroni's correction (B and D). *P < 0.05; **P < 0.01; ***P < 0.001.
Source publication
Platinum-based chemotherapy-induced peripheral neuropathy is one of the most common causes of dose reduction and discontinuation of life-saving chemotherapy in cancer treatment; it often causes permanent impairment of quality of life in cancer patients. The mechanisms that underlie this neuropathy are not defined, and effective treatment and preven...
Contexts in source publication
Context 1
... found that supplementing 50B11 cells with NAD + alone activates SIRT2 deacetylase activity, as evidenced by a decreased level of acetylated α-tubulin ( Figure 4A). Activation of SIRT2's deacetylase activity was associated with a moderate but significant increase in NER efficiency, as compared with a control cell culture that was not supplemented with NAD + ( Figure 4B). ...
Context 2
... found that supplementing 50B11 cells with NAD + alone activates SIRT2 deacetylase activity, as evidenced by a decreased level of acetylated α-tubulin ( Figure 4A). Activation of SIRT2's deacetylase activity was associated with a moderate but significant increase in NER efficiency, as compared with a control cell culture that was not supplemented with NAD + ( Figure 4B). Importantly, NAD + supplementation did not enhance NER efficiency in 50B11 Sirt2-KO cells, but the effect of NAD + supplementation on NER was restored once Sirt2 was reconstituted in the 50B11 Sirt2-KO cells ( Figure 4B). ...
Context 3
... of SIRT2's deacetylase activity was associated with a moderate but significant increase in NER efficiency, as compared with a control cell culture that was not supplemented with NAD + ( Figure 4B). Importantly, NAD + supplementation did not enhance NER efficiency in 50B11 Sirt2-KO cells, but the effect of NAD + supplementation on NER was restored once Sirt2 was reconstituted in the 50B11 Sirt2-KO cells ( Figure 4B). ...
Context 4
... for SIRT1 deacetylase activity ( Figure 4C). As shown in Figure 4D, siRNA-mediated SIRT1 inhibition did not affect NER in 50B11 cells. ...
Context 5
... for SIRT1 deacetylase activity ( Figure 4C). As shown in Figure 4D, siRNA-mediated SIRT1 inhibition did not affect NER in 50B11 cells. However, NAD + supplementation significantly enhanced NER efficiency, independently of SIRT1 activity. ...
Context 6
... KO caused a significant decrease in survival following cisplatin treatment ( Figure 5 (Fig- ure 5, B and C). We further found that expression of the enzymatically deficient HY-SIRT2 mutant did not restore cells' resistance to cisplatin-induced cytotoxicity ( Figure 5, B and C), indicating that the deacetylase activity of SIRT2 is not only critical for NER function ( Figure 4B) but is also a requisite factor for the resistance of 50B11 and PC12 cells against cisplatin-induced neuronal death. Importantly, SIRT2 expression had no effect on lung cancer cell cytotoxic response to cisplatin treatment ( SIRT2-mediated protection against CIPN depends on its function in NER. ...
Context 7
... SP pretreatment had no effect on sensitivity to cisplatin-induced cell death in empty vector-expressing Sirt2-KO 50B11 cells, which are defective in NER ( Figure 6C). SP alone was not toxic and had no effect on viability of neuronally differentiated parental 50B11 or Sirt2-KO 50B11 cells with or without SIRT2 reconstitution (Supplemental Figure 4). Together, our data suggest that SIRT2-mediated protection of neurons from cisplatin-induced cytotoxicity requires its function in TC-NER. ...
Citations
... In the present study, mice treated with cisplatin developed mechanical allodynia and cold hypersensitivity, which were sustained for at least two weeks after the last cisplatin dose, consistent with a previous study [22]. Hypersensitivity in front of mechanical stimuli is a hallmark behavioural sign of CIPN observed in rodents [39][40][41][42][43][44], reflecting the allodynia phenotype in CIPN patients. This cisplatin dosage regimen also produced cold allodynia, another symptom associated with platinum-based anticancer drugs [5,16,24], and is in accordance with earlier reports of cold sensitivity in cisplatin-treated rodents [7,28,32]. ...
Chemotherapy-induced peripheral neuropathy is a severe clinical problem frequently associated with cisplatin use. Although its pathophysiology is poorly understood, it is known that kinin receptors and the transient receptor potential ankyrin 1 (TRPA1) channel play a significant role in the peripheral neuropathy induced by cisplatin in rodents. However, the role of signalling pathways downstream from B2 kinin receptors activation and sensitisation of the TRPA1 channel remains unknown in this model. The cisplatin-induced neuropathy model caused mechanical and cold allodynia in male Swiss mice. Antagonists for kinin B2 and B1 receptors and the TRPA1 channel attenuated the painful parameters. Local sub-nociceptive doses of kinin B2 receptor (bradykinin) and TRPA1 channel (allyl isothiocyanate; AITC) agonists enhanced the painful parameters in cisplatin-treated mice, which their respective antagonists attenuated. Furthermore, we demonstrated the interaction between the kinin B2 receptor and the TRPA1 channel in cisplatin-induced peripheral neuropathy since phospholipase C (PLC) and protein kinase C epsilon (PKCε) inhibitors attenuated the increase in mechanical and cold allodynia evoked by bradykinin and AITC in cisplatin-treated mice. Therefore, regulating the activation of signalling pathways downstream from the kinin B2 receptors activation and TRPA1 channel sensitisation can mitigate the painful peripheral neuropathy decurrent of the oncology treatment with cisplatin.
... In this regard, SIRT2 directs the replication stress response (RSR), a subset of the DNA damage response (DDR), through the acetylation status of ATRIP and CDK9 ( 47 , 51 , 52 ). SIRT2 also promotes homologous recombina tion by facilita ting BRCA1-BARD1 heterodimerization through BARD1 deacetylation ( 53 ) and RPA70 and RAD51 recruitment to DSBs ( 54 ) and promotes nucleotide excision repair (NER) ( 55 ). However, a role for SIRT2 in directing NHEJ has not been established. ...
DNA-dependent protein kinase (DNA-PK) plays a critical role in non-homologous end joining (NHEJ), the predominant pathway that repairs DNA double-strand breaks (DSB) in response to ionizing radiation (IR) to govern genome integrity. The interaction of the catalytic subunit of DNA-PK (DNA-PKcs) with the Ku70/Ku80 heterodimer on DSBs leads to DNA-PK activation; however, it is not known if upstream signaling events govern this activation. Here, we reveal a regulatory step governing DNA-PK activation by SIRT2 deacetylation, which facilitates DNA-PKcs localization to DSBs and interaction with Ku, thereby promoting DSB repair by NHEJ. SIRT2 deacetylase activity governs cellular resistance to DSB-inducing agents and promotes NHEJ. SIRT2 furthermore interacts with and deacetylates DNA-PKcs in response to IR. SIRT2 deacetylase activity facilitates DNA-PKcs interaction with Ku and localization to DSBs and promotes DNA-PK activation and phosphorylation of downstream NHEJ substrates. Moreover, targeting SIRT2 with AGK2, a SIRT2-specific inhibitor, augments the efficacy of IR in cancer cells and tumors. Our findings define a regulatory step for DNA-PK activation by SIRT2-mediated deacetylation, elucidating a critical upstream signaling event initiating the repair of DSBs by NHEJ. Furthermore, our data suggest that SIRT2 inhibition may be a promising rationale-driven therapeutic strategy for increasing the effectiveness of radiation therapy.
... Peripheral neuropathy is one of the most common adverse effects of platinum-based chemotherapy drugs such as cisplatin. CIPN considerably impacts cancer treatment strategies, leading to a dose reduction or treatment discontinuation and negatively affecting the patients' quality of life [9,11,56]. The increasing number of cancer survivors and the lack of treatment to prevent or manage CIPN emphasizes the urgent need to unveil the pathophysiological mechanisms of CIPN to develop effective therapeutic strategies. ...
... Clinically, cisplatin dose is a determinant for peripheral neuropathy development [11,12,57,58]. CIPN commonly manifests as an increased perception of innocuous (allodynia) or noxious (hyperalgesia) stimuli, which are hallmark symptoms of neuropathic pain [6,8,56]. In the present study, cisplatin treatment resulted in prominent and persistent mechanical allodynia lasting at least 30 days. ...
... Changes in peripheral sensory sensations concerning cold stimuli are commonly associated with neuronal toxicity caused by antineoplastic agents such as platinum-based agents [11,12,56]. Here, we observed that six doses of cisplatin increased cold sensitivity. ...
Cisplatin is the preferential chemotherapeutic drug for highly prevalent solid tumours. However, its clinical efficacy is frequently limited due to neurotoxic effects such as peripheral neuropathy. Chemotherapy-induced peripheral neuropathy is a dose-dependent adverse condition that negatively impacts quality of life, and it may determine dosage limitations or even cancer treatment cessation. Thus, it is urgently necessary to identify pathophysiological mechanisms underlying these painful symptoms. As kinins and their B1 and B2 receptors contribute to the development of chronic painful conditions, including those induced by chemotherapy, the contribution of these receptors to cisplatin-induced peripheral neuropathy was evaluated via pharmacological antagonism and genetic manipulation in male Swiss mice. Cisplatin causes painful symptoms and impaired working and spatial memory. Kinin B1 (DALBK) and B2 (Icatibant) receptor antagonists attenuated some painful parameters. Local administration of kinin B1 and B2 receptor agonists (in sub-nociceptive doses) intensified the cisplatin-induced mechanical nociception attenuated by DALBK and Icatibant, respectively. In addition, antisense oligonucleotides to kinin B1 and B2 receptors reduced cisplatin-induced mechanical allodynia. Thus, kinin B1 and B2 receptors appear to be potential targets for the treatment of cisplatin-induced painful symptoms and may improve patients’ adherence to treatment and their quality of life.
... A recent study reported that SIRT2 can promote BRCA1-BARD1 heterodimerization via its deacetylase activity, which facilitates HR pathway and tumor suppression (Minten et al., 2021). In addition, SIRT2 can also enhance NER pathway to protect neurons from cisplatin-induced injury (Zhang et al., 2020). SIRT3mediated deacetylation participates in mitochondrial DNA repair through regulating OGG1, which protects cells against oxidative stress induced apoptosis (Cheng et al., 2013). ...
Sirtuins are a family of nicotinamide adenine dinucleotide (NAD)+-dependent histone deacetylases, comprising seven members SIRT1-SIRT7. Sirtuins have been extensively studied in regulating ageing and age-related diseases. Sirtuins are also pivotal modulators in oxidative stress and inflammation, as they can regulate the expression and activation of downstream transcriptional factors (such as Forkhead box protein O3 (FOXO3a), nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB)) as well as antioxidant enzymes, through epigenetic modification and post-translational modification. Most importantly, studies have shown that aberrant sirtuins are involved in the pathogenesis of infectious and inflammatory oral diseases, and oral cancer. In this review, we provide a comprehensive overview of the regulatory patterns of sirtuins at multiple levels, and the essential roles of sirtuins in regulating inflammation, oxidative stress, and bone metabolism. We summarize the involvement of sirtuins in several oral diseases such as periodontitis, apical periodontitis, pulpitis, oral candidiasis, oral herpesvirus infections, dental fluorosis, and oral cancer. At last, we discuss the potential utilization of sirtuins as therapeutic targets in oral diseases.
... Moreover, SIRT2 overexpression in transgenic Sirt2-knockin mice conferred protection against CIPN. 14 SIRT2, an NAD + -dependent deacetylase in the sirtuin family, has been implicated in multiple biological processes including tumor suppression, neurodegenerative disorders, lipid and glucose homeostasis, and longevity. [15][16][17][18][19] SIRT2 is found in both the nucleus and cytoplasm, 20,21 and its localization and expression are regulated through diet, oxidative stress, 20,22 and cell cycle progression. ...
... Paraffin-embedded DRG tissue sections were prepared, and slides were processed for IHC staining as previously described. 14 In brief, sections were deparaffinized and rehydrated. They were then pretreated with Target Retrieval Solution, pH 6.0 (DAKO). ...
... While our genetic mouse model has illustrated SIRT2 overexpression protects against CIPN, 14 pharmacologic activation of SIRT2 is required for clinical application. We first investigated whether pharmacologic activation of SIRT2 by NR, the NAD + precursor, can reverse CIPN in a mouse model. ...
Background
Chemotherapy-induced peripheral neuropathy represents a major impairment to the quality of life of cancer patients and is one of the most common dose-limiting adverse effects of cancer treatment. Despite its prevalence, no effective treatment or prevention strategy exists. We have previously provided genetic evidence that the NAD+ -dependent deacetylase, SIRT2, protects against cisplatin-induced peripheral neuronal cell death and neuropathy by enhancing nucleotide excision repair. In this study, we aimed to examine whether pharmacologic activation of SIRT2 would provide effective prevention and treatment of cisplatin-induced peripheral neuropathy (CIPN) without compromising tumor cell cytotoxic response to cisplatin.
Methods
Using von Frey and dynamic hot plate tests, we studied the use of nicotinamide riboside (NR) to prevent and treat CIPN in mouse model. We also performed cell survival assays to investigate the effect of NAD+ supplementation on cisplatin toxicity in neuronal and cancer cells. Lewis lung carcinoma model was utilized to examine the effect of NR treatment on in vivo cisplatin tumor control.
Results
We show that NR, an NAD+ precursor and pharmacologic activator of SIRT2, effectively prevents and alleviates CIPN in mice. We present in vitro and in vivo genetic evidence to illustrate the specific dependence on SIRT2 of NR-mediated CIPN mitigation. Importantly, we demonstrate that NAD+ mediates SIRT2-dependent neuroprotection without inhibiting cisplatin cytotoxic activity against cancer cells. NAD+ may, in fact, further sensitize certain cancer cell types to cisplatin.
Conclusions
Together, our results identify SIRT2-targeted activity of NR as a potential therapy to alleviate CIPN, the debilitating and potentially permanent toxicity.
... As a deacetylase, SIRT2 can deacetylation regulate physiological substrates and affect biological function of its downstream proteins [32][33][34]. Next, HEK293T cells underwent transfection for full-length human Myc-SIRT2 (Vector: PCMV; TAG: Myc; Species: Human). And co-immunoprecipitation was carried out to identify the proteins interacting with SIRT2 by mass spectrometry. ...
... BAG3 is a stress-induced protein and a member of the BAG family of proteins [19][20][21][22][23][24]53]. As a deacetylase, SIRT2 can induce post-translational modifications of its downstream proteins and affect the occurrence and development of a variety of diseases [32][33][34]54,55]. SIRT2 directly deacetylates key factors affecting NFATc2 and inhibits its activity, thereby suppressing pathological myocardial hypertrophy [54]. ...
Oxidative stress-associated endothelial damage is the initiation factor of cardiovascular disease, and protein posttranslational modifications play critical roles in this process. Bcl-2-associated athanogene 3 (BAG3) is a molecular chaperone regulator of the BAG family, which interacts with various proteins and influences cell survival by activating multiple pathways. BAG3 undergoes posttranslational modifications; however, research evaluating BAG3 acetylation and its regulatory mechanism is lacking. In addition, the interacting protein and regulatory mechanism of BAG3 in oxidative stress-associated endothelial damage remain unclear. Here, key molecular interactions and protein modifications of BAG3 were identified in oxidative stress-associated endothelial damage. Endothelial-specific BAG3 knockout in the mouse model starkly enhances oxidative stress-associated endothelial damage and vascular remodeling, while BAG3 overexpression in mice significantly relieves this process. Mechanistically, poly(ADP-ribose) polymerase 1 (PARP1), causing oxidative stress, was identified as a novel physiological substrate of BAG3. Indeed, BAG3 binds to PARP1's BRCT domain to promote its ubiquitination (K249 residue) by enhancing the E3 ubiquitin ligase WWP2, which leads to proteasome-induced PARP1 degradation. Furthermore, we surprisingly found that BAG3 represents a new substrate of the acetyltransferase CREB-binding protein (CBP) and the deacetylase Sirtuin 2 (SIRT2) under physiological conditions. CBP/SIRT2 interacted with BAG3 and acetylated/deacetylated BAG3's K431 residue. Finally, deacetylated BAG3 promoted the ubiquitination of PARP1. This work reveals a novel regulatory system, with deacetylation-dependent regulation of BAG3 promoting PARP1 ubiquitination and degradation via enhancing WWP2, which is one possible mechanism to decrease vulnerability of oxidative stress in endothelial cells.
... Table 1 shows cisplatin protocols in mice reported in publications in 2020/2021. Nephrotoxicity [42][43][44] was by far the most frequently studied toxicity, followed by neurotoxicity [45][46][47], ototoxicity [16,48,49], gonadotoxicity [50][51][52][53], gastrointestinal toxicity [54][55][56], muscle wasting [57][58][59] and anemia [60]. A MEDILINE/PubMed search, using keywords "cisplatin", "mouse", "toxicity" was conducted in February 2021. ...
... Mice show altered behavioral responses to thermal and mechanical stimuli and impaired performance in the novel object and place recognition tasks. However, although the induced neuropathy is mild and reversible [46], no study reported how many mice develop peripheral neuropathy (the incidence and severity of neuropathy is dose dependent). It has been recognized that models of mild neuropathy have higher inter-individual differences, which requires a higher number of animals per group [140]. ...
Cisplatin is one of the most widely used chemotherapeutic drugs in the treatment of a wide range of pediatric and adult malignances. However, it has various side effects which limit its use. Cisplatin mouse models are widely used in studies investigating cisplatin therapeutic and toxic effects. However, despite numerous promising results, no significant improvement in treatment outcome has been achieved in humans. There are many drawbacks in the currently used cisplatin protocols in mice. In the paper, the most characterized cisplatin protocols are summarized together with weaknesses that need to be improved in future studies, including hydration and supportive care. As demonstrated, mice respond to cisplatin treatment in similar ways to humans. The paper thus aims to illustrate the complexity of cisplatin side effects (nephrotoxicity, gastrointestinal toxicity, neurotoxicity, ototoxicity and myelotoxicity) and the interconnectedness and interdependence of pathomechanisms among tissues and organs in a dose- and time-dependent manner. The paper offers knowledge that can help design future studies more efficiently and interpret study outcomes more critically. If we want to understand molecular mechanisms and find therapeutic agents that would have a potential benefit in clinics, we need to change our approach and start to treat animals as patients and not as tools.
... Fourth, sirtuin-mediated deacetylation of mitochondrial proteins is associated with robust increases in cellular respiration (Kim et al., 2006;Lombard et al., 2007;Vassilopoulos et al., 2014;Yang et al., 2016); SIRT2 is one of three sirtuin proteins (SIRT1-3) with strong deacetylase activity (Feldman et al., 2013). Fifth, only SIRT1 and SIRT2 are abundantly expressed in brain tissues, with SIRT1 being highly expressed in the nucleus of neuronal cells (Jayasena et al., 2016) and SIRT2 primarily enriched in mature OLs (Liu et al., 2019;Zhang et al., 2020). Interestingly, SIRT2 expression changes over time, accumulating in the aging CNS (Maxwell et al., 2011). ...
Neurons require mechanisms to maintain ATP homeostasis in axons, which are highly vulnerable to bioenergetic failure. Here, we elucidate a transcellular signaling mechanism by which oligodendrocytes support axonal energy metabolism via transcellular delivery of NAD-dependent deacetylase SIRT2. SIRT2 is undetectable in neurons but enriched in oligodendrocytes and released within exosomes. By deleting sirt2, knocking down SIRT2, or blocking exosome release, we demonstrate that transcellular delivery of SIRT2 is critical for axonal energy enhancement. Mass spectrometry and acetylation analyses indicate that neurons treated with oligodendrocyte-conditioned media from WT, but not sirt2-knockout, mice exhibit strong deacetylation of mitochondrial adenine nucleotide translocases 1 and 2 (ANT1/2). In vivo delivery of SIRT2-filled exosomes into myelinated axons rescues mitochondrial integrity in sirt2-knockout mouse spinal cords. Thus, our study reveals an oligodendrocyte-to-axon delivery of SIRT2, which enhances ATP production by deacetylating mitochondrial proteins, providing a target for boosting axonal bioenergetic metabolism in neurological disorders.
... The deacetylase SIRT2 is an important member of the Sirtuin family and involved in various biological processes by deacetylating various physiological substrates [10][11][12][13][14]. Although evidence suggests that SIRT2 is a protective factor against myocardial hypertrophy [15,16], the role of SIRT2 in oxidative stress-induced vascular injury and its regulatory substrates remains unclear. ...
... As an NAD + -dependent deacetylase, SIRT2 plays roles in various biological processes that include lipid and glucose homeostasis, tumor suppression, and neurodegenerative diseases [10][11][12][13][14]. Interestingly, we found that SIRT2 protected against vascular damage through the SIRT2-WWP2-PARP1 pathway. ...
Poly(ADP-ribose) polymerase 1 (PARP1) has a major regulatory role in cardiovascular disease. However, inhibiting PARP1 activity does not significantly improve clinical outcomes of cardiovascular disease, which suggests that the regulatory mechanism of PARP1 in cardiovascular disease is unclear. Here, we focused on deacetylation regulatory mechanisms of PARP1 and crosstalk of PARP1 post-translational modifications. We uncovered the crucial molecular interactions and protein modifications of deacetylase Sirtuin 2 (SIRT2) and PARP1 in vascular damage. The results showed that SIRT2 was involved in this process and oxidative stress damage factor PARP1 was a novel physiological substrate of SIRT2. SIRT2 interacted with PARP1 at the PARP-A-helical domain and deacetylated the K249 residue of PARP1. Furthermore, SIRT2 promoted ubiquitination of the K249 residue of PARP1 via mobilization of the E3 ubiquitin ligase WW domain-containing protein 2 (WWP2), which led to proteasome-mediated degradation of PARP1. Knockout of SIRT2 in mice and cells increased PARP1 acetylation and decreased PARP1 ubiquitination, which in turn aggravated oxidative stress-induced vascular injury and remodeling. Conversely, overexpression of SIRT2 in mice and cells decreased PARP1 acetylation, increased PARP1 ubiquitination, and relieved oxidative stress-induced vascular injury and remodeling. Overall, this study revealed a previously unrecognized mechanistic link between SIRT2 and PARP1 in the regulation of oxidative stress-induced vascular injury.
... This condition is one of the most common causes of chemotherapy dose reduction and discontinuation. Cisplatin induces SIRT2 nuclear accumulation in dorsal root ganglia neurons, allowing SIRT2 to participate in the repair of cisplatin-generated DNA damage (74). Multiple studies have shown that SIRT2 contributes to the stemness of cancer stem cells (CSCs), which provides a further link between SIRT2 and chemoresistance in NSCLC (75,76). ...
Non-small cell lung cancer (NSCLC) is one of the most devastating cancer types, accounting for >80% of lung cancer cases. The median relative survival time of patients with NSCLC is <1 year. Lysine acetylation is a major post-translational modification that is required for various biological processes, and abnormal protein acetylation is associated with various diseases, including NSCLC. Protein deacetylases are currently considered cancer permissive partly due to malignant cells being sensitive to deacetylase inhibition. Sirtuin 2 (SIRT2), a primarily cytosolic nicotinamide adenine dinucleotide-dependent class III protein deacetylase, has been shown to catalyze the removal of acetyl groups from a wide range of proteins, including tubulin, ribonucleotide reductase regulatory subunit M2 and glucose-6-phosphate dehydrogenase. In addition, SIRT2 is also known to possess lysine fatty deacylation activity. Physiologically, SIRT2 serves as a regulator of the cell cycle and of cellular metabolism. It has been shown to play important roles in proliferation, migration and invasion during carcinogenesis. It is notable that both oncogenic and tumor suppressive functions of SIRT2 have been described in NSCLC and other cancer types, suggesting a context-specific role of SIRT2 in cancer progression. In addition, inhibition of SIRT2 exhibits a broad anticancer effect, indicating its potential as a therapeutic for NSCLC tumors with high expression of SIRT2. However, due to the diverse molecular and genetic characteristics of NSCLC, the context-specific function of SIRT2 remains to be determined. The current review investigated the functions of SIRT2 during NSCLC progression with regard to its regulation of metabolism, stem cell-like features and autophagy.
