RESUMEN

The nucleolar enzyme sirtuin 7 (SIRT7) promotes cancer progression in certain malignancies, likely in part by controlling ribosome biosynthesis. Recently, we discovered that SIRT7 destabilizes the cyclin dependent kinase inhibitor 2A (CDKN2A, known as ARF) within the nucleolus, aiding cancer progression. We propose that targeting nucleolar SIRT7 offers promise for new anti-cancer therapies.

RESUMEN

BACKGROUND: Sirtuin 7 (SIRT7), as a nicotinamide adenine dinucleotide-dependent protein/histone deacetylase, has been implicated in the pathogenesis of cardiovascular diseases. However, whether SIRT7 is related to hypertension remains largely unclear. Thus, this study aims to explore the effects and correlation between SIRT7 and hypertension. METHODS: A total of 72 patients with essential hypertension and 82 controls with non-hypertension were recruited at Beijing Tongren Hospital Affiliated with Capital Medical University from July 2022 to June 2023. Plasma SIRT7 expression was measured using enzyme-linked immunosorbent assay analysis. Clinical baseline characteristics, laboratory measurements, echocardiographic data, and medical therapy were collected. RESULTS: Plasma levels of SIRT7 were lower in hypertensive patients compared with non-hypertensive patients [0.97 (0.58-1.30) vs. 1.24 (0.99-1.46) ng/mL, P < 0.001, respectively]. Furthermore, compared with the low SIRT7 group, there were lower levels of systolic blood pressure, hyperlipidemia, and the ultrasonic electrocardiogram parameters left ventricular end-diastolic diameter and left atrial in diastole in the high SIRT7 group (P < 0.05, respectively). More importantly, multivariate logistic regression analyses indicated that plasma SIRT7 was a predictor of hypertension [OR: 0.06, 95 % CI (0.02-0.19), P < 0.001]. Receiver operating characteristics curve analysis revealed that the optimal cutoff value for plasma SIRT7 levels in detecting hypertension was determined as 0.85 ng/mL with a sensitivity of 73.6 % and a specificity of 89.0 %. The area under the curve for SIRT7 was 0.821 (95 % CI, 0.751-0.878; P < 0.001). CONCLUSION: Plasma levels of SIRT7 are decreased in patients with essential hypertension, implying its potential as a biomarker for diagnosing essential hypertension..

Asunto(s)

Hipertensión Esencial , Sirtuinas , Humanos , Femenino , Masculino , Persona de Mediana Edad , Hipertensión Esencial/sangre , Sirtuinas/sangre , Adulto , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Curva ROC , Hipertensión/sangre

RESUMEN

The signal transducer and activator of transcription 1 (STAT1) plays a crucial role in regulating tumor progression. However, the mechanisms governing its phosphorylation and biological functions remain incompletely understood. Here, we present compelling evidence indicating that knockdown of SIRT7 inhibits Smurf1-induced ubiquitination of STAT1, consequently impeding the proteasome pathway degradation of STAT1. This inhibition leads to increased stability of STAT1 and enhanced binding to JAK1. Importantly, SIRT7 exerts a negative regulatory effect on STAT1 activation and IFN-γ/STAT1 signaling in hepatocellular carcinoma (HCC). Etoposide treatment not only facilitates STAT1 activation but also downregulates SIRT7 expression. Notably, knockdown of STAT1 in SIRT7-deficient cells attenuates the increase in cell apoptosis induced by Etoposide treatment. In conclusion, our data shed light on the intricate interplay between ubiquitination, STAT1, SIRT7, and Smurf1, elucidating their impact on STAT1-related signaling. These insights contribute to a more comprehensive understanding of the molecular mechanisms involved in STAT1 regulation and suggest potential avenues for the development of targeted therapies against cancer.

Asunto(s)

Carcinoma Hepatocelular , Neoplasias Hepáticas , Sirtuinas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Etopósido , Línea Celular Tumoral , Transducción de Señal , Fosforilación , Factor de Transcripción STAT1/metabolismo , Sirtuinas/metabolismo

RESUMEN

Hypertension is one of the leading causes of chronic kidney disease characterized with renal fibrosis. This study aimed to investigate roles and mechanisms of sirtuin 7 (SIRT7) in hypertensive renal injury. Mini-pumps were implanted to male C57BL/6 mice to deliver angiotensin (Ang) Ⅱ (1.5 mg/kg/d) or saline for 2 weeks. Ang Ⅱ infusion resulted in marked increases in systolic blood pressure levels, renal ferroptosis and interstitial fibrosis in hypertensive mice, concomitantly with downregulated SIRT7 and Krüppel-like factor 15 (KLF15) levels. Notably, administration of recombinant adeno-associated virus-SIRT7 or ferroptosis inhibitor ferrostatin-1 effectively mitigated Ang Ⅱ-triggered renal ferroptosis, epithelial-mesenchymal transition (EMT), interstitial fibrosis, renal functional and structural injury in hypertensive mice by blunting the KIM-1/NOX4 signaling and enforcing the KLF15/Nrf2 and xCT/GPX4 signaling, respectively. In primary cultured mouse renal tubular epithelial cells (TECs), Ang Ⅱ pretreatment led to repressed SIRT7 expression and augmented ferroptosis as well as partial EMT, which were substantially antagonized by rhSIRT7 or ferrostatin-1 administration. Additionally, both Nrf2 inhibitor ML385 and KLF15 siRNA strikingly abolished the rhSIRT7-mediated beneficial roles in mouse renal TECs in response to Ang Ⅱ with reduced expression of Nrf2, xCT and GPX4. More importantly, ML385 administration remarkably amplified Ang Ⅱ-mediated ROS generation, lipid peroxidation and ferroptosis in renal TECs, which were significantly reversed by ferrostatin-1. In conclusion, SIRT7 alleviates renal ferroptosis, lipid peroxidation, and partial EMT under hypertensive status by facilitating the KLF15/Nrf2 signaling, thereby mitigating renal fibrosis, injury and dysfunction. Targeting SIRT7 signaling serves as a promising strategy for hypertension and hypertensive renal injury.

Asunto(s)

Ferroptosis , Hipertensión , Enfermedades Renales , Sirtuinas , Animales , Masculino , Ratones , Angiotensina II/metabolismo , Ferroptosis/genética , Fibrosis , Hipertensión/metabolismo , Riñón/metabolismo , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Sirtuinas/genética , Sirtuinas/metabolismo

RESUMEN

Cell senescence is a state of limited cell proliferation during a stress response or as part of a programmed process. When a senescent cell stops dividing, maintaining metabolic activity contributes to cellular homeostasis maintenance. In this process, the cell cycle is arrested at the G0/G1 phase. p16INK4A protein is a key regulator of this process via its cyclin­dependent kinase inhibitor (CDKI) function. CDKI 2A (CDKN2A)/p16 gene expression is regulated by DNA methylation and histone acetylation. Sirtuins (SIRTs) are nicotinamide dinucleotide (NAD+)­dependent deacetylases that have properties which prevent diseases and reverse certain aspects of aging (such as immune, metabolic and cardiovascular diseases). By performing quantitative PCR, Western blot, ChIP, and siRNAs assays, in this study it was demonstrated that CDKN2A/p16 gene transcriptional activation and repression were accompanied by selective deposition and elimination of histone acetylation during the senescence of MRC5 cells. Specifically, significant H3K9Ac and H3K18Ac enrichment in cells with a senescent phenotype concomitant with CDKN2A/p16 gene overexpression was demonstrated compared with the non­senescent phenotype. Furthermore, the presence of H3K18Ac in deacetyl­transferase SIRT7 knockdown MRC5 cells allowed CDKN2A/p16 promoter activation. These results suggested that SIRT7 served as a critical component of an epigenetic mechanism involved in senescence mediated by the CDKN2A/p16 gene.

Asunto(s)

Inhibidor p16 de la Quinasa Dependiente de Ciclina , Sirtuinas , Senescencia Celular/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , Histonas/metabolismo , NAD/metabolismo , Niacinamida , Sirtuinas/genética , Sirtuinas/metabolismo

RESUMEN

Cardiovascular disorders and associated renal diseases account for the main cause of morbidity and mortality worldwide, necessitating the development of novel effective approaches for the prevention and treatment of cardiorenal diseases. Mammalian sirtuins (SIRTs) function as nicotinamide adenine dinucleotide (NAD+)-dependent protein/histone deacetylases. Seven members of SIRTs share a highly invariant catalytic core domain responsible for the specific enzymatic activity. Intriguingly, the broad distribution of SIRTs and alternative isoforms implicate its distinct functions in diverse cardiac and renal cells and tissue types. Notably, SIRT7 has been shown to exert beneficial effects in cardiorenal physiology and pathophysiology via modulation of senescence, DNA damage repair, ribosomal RNA synthesis, protein biosynthesis, angiogenesis, apoptosis, superoxide generation, cardiorenal metabolism, and dysfunction. Furthermore, SIRT7 has emerged as a critical modulator of a broad range of cellular activities including oxidative stress, inflammation response, endoplasmic reticulum stress, and mitochondrial homeostasis, which are all of great significance in postponing the progression of cardiorenal diseases. More importantly, SIRT7 has been implicated in cardiorenal hypertrophy, fibrosis, remodeling, heart failure, atherosclerosis as well as renal acid-base and electrolyte homeostasis as an essential regulator. In this article, we focus on the involvement in cardiorenal physiology and pathophysiology, diverse actions and underlying mechanisms of the SIRT7 signaling, highlighting its updated research progress in heart failure, atherosclerosis, diabetic nephropathy and other cardiorenal diseases. Targeting SIRT7 signaling could be potentially exploited as a therapeutic strategy aiming to prevent and treat cardiorenal diseases.

Asunto(s)

Aterosclerosis , Cardiopatías , Insuficiencia Cardíaca , Hipertensión Renal , Sirtuinas , Animales , Cardiopatías/tratamiento farmacológico , Mamíferos/metabolismo , Nefritis , Sirtuinas/metabolismo

RESUMEN

Chronic hepatitis B virus (HBV) infection is a significant public health burden worldwide. HBV covalently closed circular DNA (cccDNA) organized as a minichromosome in nucleus is responsible for viral persistence and is the key obstacle for a cure of chronic hepatitis B (CHB). Recent studies suggest cccDNA transcription is epigenetically regulated by histone modifications, especially histone acetylation and methylation. In the present study, we identified transcriptionally active histone succinylation (H3K122succ) as a new histone modification on cccDNA minichromosome by using cccDNA ChIP-Seq approach. Silent mating type information regulation 2 homolog 7 (SIRT7), as an NAD+-dependent histone desuccinylase, could bind to cccDNA through interaction with HBV core protein where it catalyzed histone 3 lysine 122 (H3K122) desuccinylation. Moreover, SIRT7 acts cooperatively with histone methyltransferase, suppressor of variegation 3-9 homolog 1 (SUV39H1) and SET domain containing 2 (SETD2) to induce silencing of HBV transcription through modulation of chromatin structure. Our data improved the understanding of histone modifications of the cccDNA minichromosome, thus transcriptional silencing of cccDNA may represent a novel antiviral strategy for the prevention or treatment of HBV infection.

Asunto(s)

Catálisis , ADN Circular/metabolismo , Histona Metiltransferasas/genética , Histonas/metabolismo , Sirtuinas/metabolismo , ADN Viral/genética , Hepatitis B/prevención & control , Hepatitis B/terapia , Hepatitis B/virología , Virus de la Hepatitis B/patogenicidad , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/prevención & control , Humanos , Sirtuinas/genética , Transcripción Genética/genética , Replicación Viral/genética

RESUMEN

Long non­coding RNAs (lncRNAs) have been discovered to participate in the progression of various types of disease and may be a promising biomarker for atherosclerosis (AS). The present study aimed to investigate the regulatory mechanisms of the lncRNA, small nucleolar RNA host gene 7­003 (SNHG7­003), on the proliferation, migration and invasion of vascular smooth muscle cells (VSMCs). VSMCs were first stimulated with oxidized low­density lipoprotein (ox­LDL) to simulate AS in a high fat environment. The expression levels of SNHG7­003, microRNA (miRNA/miR)­1306­5p and sirtuin 7 (SIRT7) were analyzed by reverse transcription­quantitative PCR and the effects of each of these factors on VSMC proliferation, migration and invasion were determined by Cell Counting Kit­8, wound healing and Transwell assays, respectively. Western blot analysis was also used to analyze the protein expression levels of α­smooth muscle actin (α­SMA), matrix metalloproteinase (MMP)2 and MMP9. The interactions between SNHG7­003 or SIRT7 and miR­1306­5p were determined using dual­luciferase reporter assays. The results revealed that the SNHG7­003 expression levels were downregulated in VSMCs exposed to ox­LDL, while the overexpression (OE) of SNHG7­003 significantly inhibited the proliferation, migration and invasion of VSMCs induced by ox­LDL. Transfection with miR­1306­5p mimic abrogated the effects of the inhibitory effects induced by SNHG7­003 OE. SIRT7 was validated to be a target gene of miR­1306­5p, exhibiting similar inhibitory effects as SNHG7­003 in AS. It was also discovered to be involved in the regulatory effects of the SNHG7­003/miR­1306­5p axis in VSMCs. On the whole, the findings of the present study indicate that SNHG7­003 may inhibit the proliferation, migration and invasion of VSMCs via the miR­1306­5p/SIRT7 signaling pathway. These findings may provide a novel basis for the development of treatment strategies for AS.

Asunto(s)

Movimiento Celular , Proliferación Celular , MicroARNs/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , ARN Largo no Codificante/metabolismo , Transducción de Señal , Sirtuinas/metabolismo , Línea Celular , Humanos , MicroARNs/genética , ARN Largo no Codificante/genética , Sirtuinas/genética

RESUMEN

This study investigated the functional role of p53-lincRNA-p21 in atherosclerosis (AS) by mediating the microRNA-17-5p (miR-17-5p)/SIRT7 axis. Peripheral blood was collected from AS patients, and an ApoE-/- mouse model of AS (AS-M) was induced by high-fat diet. The relationship among p53, lincRNA-p21, miR-17-5p, and SIRT7 was validated, and their effects on AS progression and vascular smooth muscle cell (VSMC) functions were analyzed using gain- and loss-of-function experiments in AS mice and human and mouse VSMCs. p53, lincRNA-p21, and SIRT7 were downregulated, and miR-17-5p was upregulated in AS-M and peripheral blood of AS patients. p53 positively regulated lincRNA-p21, while miR-17-5p, reversely targeted by lincRNA-p21, could target SIRT7. Overexpressing p53, lincRNA-p21, or SIRT7 contributed to impaired proliferation and promoted apoptosis of VSMCs in vitro as well as reducing the vulnerable plaque and lipid accumulation in AS mice. Collectively, p53-dependent lincRNA-p21 expression downregulated miR-17-5p, which consequently protecting against AS progression via SIRT7 elevation. Graphical abstract Collectively, p53-dependent lincRNA-p21 expression downregulated miR-17-5p, whichconsequently protecting against AS progression via SIRT7 elevation.

Asunto(s)

Apoptosis , Aterosclerosis/enzimología , Proliferación Celular , MicroARNs/metabolismo , Músculo Liso Vascular/enzimología , Miocitos del Músculo Liso/enzimología , ARN Largo no Codificante/metabolismo , Sirtuinas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Anciano , Animales , Aterosclerosis/genética , Aterosclerosis/patología , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , MicroARNs/genética , Persona de Mediana Edad , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , ARN Largo no Codificante/genética , Transducción de Señal , Sirtuinas/genética , Proteína p53 Supresora de Tumor/genética , Regulación hacia Arriba

RESUMEN

Increasing evidence has indicated the roles of sirtuin 7 (SIRT7) in numerous human cancers. However, the effects and the clinical significance of SIRT7 in human lung cancer is largely unknown. The present research demonstrated that SIRT7 was increased in human lung cancer tumor tissues. SIRT7 upregulation was associated with clinicopathological characteristics of lung cancer malignancy including positive lymph node metastasis, high pathologic stage and large tumor size. SIRT7 was also upregulated in human non­small cell lung cancer (NSCLC) cell lines. Furthermore SIRT7­overexpressed A549 (A549­SIRT7) and SIRT7­knocked down H292 (H292­shSIRT7) human NSCLC cell lines were established. Using these NSCLC cells and xenograft mouse models, it was revealed that SIRT7 overexpression markedly promoted growth and G1 to S cell cycle phase transition as well as migration, invasion and distant lung metastasis in A549 NSCLC cells, whereas SIRT7 knockdown suppressed these processes in H292 NSCLC cells. Mechanistically, in A549 NSCLC cells, SIRT7 overexpression significantly activated not only protein kinase B (AKT) signaling but also extracellular signal­regulated kinase 1/2 (ERK1/2) signaling. SIRT7 overexpression also significantly downregulated cyclin­dependent kinase (CDK) inhibitors including p21 and p27 as well as upregulated cyclins including cyclin D1 and cyclin E1, and CDKs including CDK2 and CDK4. Notably, the epithelial­mesenchymal transition (EMT) process of A549 NSCLC cells was facilitated by SIRT7 overexpression, as evidenced by E­cadherin epithelial marker downregulation and mesenchymal markers (N­cadherin, vimentin, Snail and Slug) upregulation. In addition, SIRT7 knockdown in H292 NSCLC cells exhibited the opposite regulatory effects. Moreover, inhibition of AKT signaling abated the promoting effects of SIRT7 in NSCLC cell proliferation and EMT progression. The present data indicated that SIRT7 accelerated human NSCLC cell growth and metastasis possibly by promotion of G1 to S­phase transition and EMT through modulation of the expression of G1­phase checkpoint molecules and EMT markers as well as activation of AKT and ERK1/2 signaling. SIRT7 could be an innovative potential target for human NSCLC therapy.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Sirtuinas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Carcinoma de Pulmón de Células no Pequeñas/secundario , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Regulación hacia Abajo , Transición Epitelial-Mesenquimal/genética , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Pulmón/patología , Pulmón/cirugía , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Sistema de Señalización de MAP Quinasas/genética , Masculino , Ratones , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neumonectomía , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sirtuinas/genética , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Background: Sirtuin 7 (SIRT7), a protein-coding gene whose abnormal expression and function are associated with carcinogenesis. However, the prognosis of SIRT7 in different breast cancer subtypes and its correlation with tumor-infiltrating lymphocytes remain unclear. Methods: The expression and survival data of SIRT7 in patients with breast cancer were analyzed using Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interaction Analysis (GEPIA), The Human Protein Atlas (HPA), UALCAN, Breast Cancer Gene-Expression Miner (BC-GenExMiner), and Kaplan-Meier plotter databases. Also, the expression correlations between SIRT7 and immune infiltration gene markers were analyzed using TIMER and further verified the results using immunohistochemistry. Results: SIRT7 exhibited higher expression levels in breast cancer tissues than the adjacent normal tissues. SIRT7 expression was significantly correlated with sample type, subclass, cancer stage, menopause status, age, nodal status, estrogen receptor (ER), progesterone receptor (PR), and triple-negative status. High SIRT7 expression was associated with poor prognosis in breast cancer-luminal A [overall survival (OS): hazard ratio (HR) = 1.54, p = 1.70e-02; distant metastasis-free survival (DMFS): HR = 1.56, p = 2.60e-03]. Moreover, the expression of SIRT7 was positively correlated with the expression of IRF5 (M1 macrophages marker, r = 0.165, p = 1.13e-04) and PD1 (T cell exhaustion marker, r = 0.134, p = 1.74e-03). These results suggested that the expression of SIRT7 was related to M1 macrophages and T cell exhaustion infiltration in breast cancer-luminal. Conclusions: These findings demonstrate that the high expression of SIRT7 indicates poor prognosis in breast cancer as well as increased immune infiltration levels of M1 macrophages and T cell exhaustion in breast cancer-luminal. Thus, SIRT7 may serve as a candidate prognostic biomarker for determining prognosis associated with immune infiltration in breast cancer-luminal.

RESUMEN

BACKGROUND: Sirtuin-7 (SIRT7) is associated with the maintenance of tumorigenesis. However, its functional roles and oncogenic mechanisms in prostate cancer (PCa) are poorly understood. Here, we investigated the roles and underlying molecular mechanisms of SIRT7 in PCa cell growth and androgen-induced autophagy. METHODS: The LNCap and 22Rv1 PCa cell lines were subjected to quantitative reverse transcription (RT)-PCR to characterize their genes encoding SIRT7, AR, and SMAD4. The proteins produced from these genes were quantified by western blotting and immunoprecipitation analysis. SIRT7-depleted cells were produced by transfection with plasmid vectors bearing short hairpin RNAs against SIRT7. The proliferation of each cell line was assessed by CCK8 and EdU assays. Autophagic flux was tracked by mRFP-GFP-LC3 adenovirus under an immunofluorescence microscope. Apoptosis was evaluated by flow cytometry. Tumors were induced in mouse axillae by injection of the cell lines into mice. Tumor morphology was examined by immunohistochemistry and relative tumor growth and metastases were compared by a bioluminescence-based in vivo imaging system. RESULTS: SIRT7 depletion significantly inhibited cell proliferation, androgen-induced autophagy, and invasion in LNCap and 22Rv1 cells (in vitro) and mouse xenograft tumors induced by injection of these cells (in vivo). SIRT7 knockdown also increased the sensitivity of PCa cells to radiation. Immunohistochemical analysis of 93 specimens and bioinformatic analysis revealed that SIRT7 expression was positively associated with androgen receptor (AR). Moreover, the AR signal pathway participated in SIRT7-mediated regulation of PCa cell proliferation, autophagy, and invasion. SIRT7 depletion downregulated the AR signal pathway by upregulating the level of SMAD4 protein in PCa cells. CONCLUSION: SIRT7 plays an important role in the development and progression of human PCa and may be a promising prognostic marker for prostate cancer.

Asunto(s)

Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Transducción de Señal , Sirtuinas/genética , Sirtuinas/metabolismo , Animales , Apoptosis/genética , Autofagia , Biomarcadores de Tumor , Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Masculino , Ratones , Metástasis de la Neoplasia , Pronóstico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Tolerancia a Radiación/genética , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

The sirtuin family comprises seven NAD+-dependent histone deacetylases named SIRT1 to SIRT7. The least investigated SIRT7 is currently considered as a promising therapeutic target for cardiovascular diseases, diabetes and different types of cancer. So far, its structure was not experimentally resolved, except of a fragment of its N-terminus. The aim of this study was to create in silico model of SIRT7 containing its core together with N-terminus, which is known to affect the enzyme's catalytic activity and to find pockets that could be targeted by structure-based virtual screening. Homology model of SIRT7 was prepared using X-ray structures of other sirtuins and a resolved fragment of the N-terminus of SIRT7 as templates. All atom-unbiased molecular dynamics simulations were performed. It was found that N-terminus of SIRT7 remains in spatial proximity of the catalytic core for considerable fraction of time, and therefore, it may affect its catalytic activity by helping the enzyme to hold the substrate peptide. It may also participate in holding and release of the cofactor. Preferred orientations of NAD+ and acetyl-lysine inside SIRT7 were found, with all components forming a stable complex. Molecular dynamics provided an ensemble of conformations that will be targeted with virtual screening. Reliable in silico structure of SIRT7 will be a useful tool in searching for its inhibitors, which can be potential drugs in cancer treatment.Communicated by Ramaswamy H. Sarma.

Asunto(s)

Sirtuinas , Simulación por Computador , Humanos , Lisina , Sirtuinas/química , Relación Estructura-Actividad

RESUMEN

Sirtuin-7 is an evolutionarily conserved NAD-dependent deacetylase, which serves an important role in carcinogenesis. However, the potential mechanism of sirtuin-7 in endometrial cancer has not yet been investigated. The purpose of the present study was to investigate whether sirtuin-7 exhibits inhibitory effects on endometrial cancer cells. The potential mechanisms mediated by sirtuin-7 in endometrial cancer cells were also investigated. The expression levels of sirtuin-7 in endometrial cancer cells were compared with normal endometrial cells using western blotting. The results demonstrated that sirtuin-7 is overexpressed in endometrial cancer cells compared with normal endometrial cells. The downregulation of sirtuin-7 inhibited the growth and invasiveness of endometrial cancer cells. The knockdown of sirtuin-7 was observed to increase the sensitivity of the endometrial cancer cells to cisplatin treatment in vitro. An investigation into the potential molecular mechanism demonstrated that sirtuin-7 knockdown promoted the apoptosis of endometrial cancer cells by regulating the nuclear factor (NF)-κB signaling pathway. The knockdown of sirtuin-7 inhibited NF-κB expression and resulted in a decrease in the expression of NF-κB target proteins that are anti-apoptotic: Bcl-xl, Bcl-2 and Mcl-1. Sirtuin-7 knockdown also resulted in an increase of the NF-κB target proteins that are pro-apoptotic: Caspase-3, Bad and Bax. In conclusion, the present study demonstrated that sirtuin-7 knockdown was able to markedly inhibit the growth of endometrial cancer cells, suggesting that sirtuin-7 may be a potential therapeutic target for endometrial cancer therapy.

RESUMEN

Sirtuin7 (Sirt7) is a member of the Sir2 histone deacetylase family that functions in a number of physiological processes, including cellular metabolism, ageing and apoptosis. Several studies have indicated that Sirt7 may serve a vital role in promoting the development of cancer. However, to the best of our knowledge, its function in glioma progression has not been demonstrated. The present study revealed that Sirt7 expression was upregulated in human glioma tissues and that the high expression level of Sirt7 was positively associated with glioma malignancy. Further results indicated that the suppression of Sirt7 expression could inhibit the activation of phosphorylated extracellular signal-regulated kinase (p-ERK) concomitantly with decreased expression of cyclin-dependent kinase 2 in glioma cells. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) inhibited when Sirt7 was downregulated by siRNA interference in glioma cell lines. The findings of the present study indicated that Sirt7 affects the malignancy of glioma cells mainly in promoting glioma proliferation and invasion through ERK and STAT3 signaling. Thus, Sirt7 may function as a valuable target for the treatment of human glioma.

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is a severe, incurable, age-associated respiratory disorder that has gained significance because of its unknown etiology and lack of therapeutic approaches. IPF causes maximum damage to the alveolar epithelial cells, thereby leading to lung remodeling and initiating epithelial to mesenchymal transition (EMT). The actual molecular mechanisms underlying IPF still remain unclear, and knowledge about these mechanisms would be helpful in its diagnosis. Sirtuins (Sirt) are class of NAD+-dependent proteins, widely known to exert positive and protective effects on age-related diseases such as diabetes, cancer, and so on, and are also involved in regulating IPF. The sirtuin family comprises of seven members (Sirt1 to Sirt7), out of which Sirt1, Sirt3, Sirt6, and Sirt7 exert positive effects on IPF. Sirt1 is associated with aging and inhibits cellular senescence and fibrosis. Sirt1 is well recognized in controlling pulmonary fibrosis and is also considered as a prime positive mediator of EMT. The expressions of Sirt3 protein tend to decline in IPF patients; hence it is known as an anti-fibrotic protein. Sirt6 indeed has been proven to reduce EMT during IPF. Decreased levels of Sirt7 during IPF regulate lung fibroblasts. Hence, active levels of Sirt1, Sirt3, Sirt6, and Sirt7 can be attractive target models to elucidate a novel potential therapeutic approach for IPF. In this prospect, we have discussed the role of Sirtuins in pulmonary fibrosis by exploring the recent research evidence that highlight the role of sirtuins and also describes their protective effects.

RESUMEN

BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common malignancies and has a poor prognosis. The epithelial-to-mesenchymal transition (EMT) is crucial for increasing the metastasis of OSCC. Recently, studies have indicated that sirtuin7 (SIRT7) is implicated in tumor genesis; however, the potential role of SIRT7 in the EMT and metastasis of OSCC has not been reported. METHODS: We investigated the cellular responses to SIRT7 silencing or overexpression in OSCC cell lines by wound healing assay, migration and invasion assay, western blotting, immunofluorescence and immunohistochemistry. RESULTS: In the present study, we found that SIRT7 was significantly downregulated in OSCC cell lines and human OSCC/OSCC tissues with lymph node metastasis. Overexpression of SIRT7 decreased the proliferation and invasion of OSCC cells in vitro, whereas SIRT7 knockdown significantly increased OSCC cell growth and invasion. Upregulation of SIRT7 concomitantly increased the expression of E-cadherin, and decreased the expression of mesenchymal markers. SIRT7 overexpression also reduced the level of acetylated SMAD4 in OSCC cells. Moreover, SIRT7 overexpression significantly inhibited OSCC lung metastasis in vivo. CONCLUSION: Together, these findings suggested that SIRT7 suppressed EMT in OSCC metastasis by promoting SMAD4 deacetylation.

Asunto(s)

Carcinoma de Células Escamosas/genética , Neoplasias de la Boca/genética , Sirtuinas/genética , Proteína Smad4/genética , Carcinoma de Células Escamosas/patología , Transición Epitelial-Mesenquimal , Humanos , Neoplasias de la Boca/patología , Metástasis de la Neoplasia , Pronóstico , Sirtuinas/metabolismo , Proteína Smad4/metabolismo

RESUMEN

In the yeast Saccharomyces cerevisiae, genomic instability in rDNA repeat sequences is an underlying cause of cell aging and is suppressed by the chromatin-silencing factor Sir2. In humans, rDNA instability is observed in cancers and premature aging syndromes, but its underlying mechanisms and functional consequences remain unclear. Here, we uncovered a pivotal role of sirtuin 7 (SIRT7), a mammalian Sir2 homolog, in guarding against rDNA instability and show that this function of SIRT7 protects against senescence in primary human cells. We found that, mechanistically, SIRT7 is required for association of SNF2H (also called SMARCA5, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A, member 5), a component of the nucleolar heterochromatin-silencing complex NoRC, with rDNA sequences. Defective rDNA-heterochromatin silencing in SIRT7-deficient cells unleashed rDNA instability, with excision and loss of rDNA gene copies, which in turn induced acute senescence. Mounting evidence indicates that accumulation of senescent cells significantly contributes to tissue dysfunction in aging-related pathologies. Our findings identify rDNA instability as a driver of mammalian cellular senescence and implicate SIRT7-dependent heterochromatin silencing in protecting against this process.

Asunto(s)

Neoplasias Óseas/patología , Senescencia Celular , ADN Ribosómico/genética , Epigénesis Genética , Inestabilidad Genómica , Osteosarcoma/patología , Sirtuinas/metabolismo , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Osteosarcoma/genética , Osteosarcoma/metabolismo , Sirtuinas/genética , Transcripción Genética , Células Tumorales Cultivadas

RESUMEN

Sirtuin 7 (Sirt7) is a member of the sirtuin protein family and is implicated in various carcinomas; however, the function of Sirt7 in colorectal carcinoma (CRC) remains unclear. The present study aimed to explore the biological function of Sirt7 in CRC tissues and cell lines, and to investigate the potential underlying mechanism by performing reverse transcription-quantitative polymerase chain reaction analyses, western blot analyses, luciferase reporter assays, cell proliferation and invasion assays. It was demonstrated that Sirt7 presented a higher expression in CRC tissues and cell lines compared with that in normal tissues and cells, and this higher expression was correlated with the tumor size, the tumor, node and metastasis stage and distant metastasis. Knockdown of Sirt7 repressed the proliferation ability of SW620 and HCT116 cells in vitro, while ectopic expression of Sirt7 increased the epithelial-mesenchymal transition and invasion in HT29 and SW480 cells. Notably, these functional effects of Sirt7 were exerted through the repression of E-cadherin. Thus, the data of the present study indicated a novel mechanistic role for Sirt7 as an oncogene in CRC malignancy, and Sirt7 may be a potential therapeutic target.

RESUMEN

BACKGROUND: SIRT7 is one of the histone deacetylases and is NAD-dependent. It forms a complex with ETS-like transcription factor 4 (ELK4), which deacetylates H3K18ac and works as a transcriptional suppressor. Overexpression of SIRT7 and deacetylation of H3K18ac have been shown to be associated with aggressive clinical behavior in some cancers, including hepatocellular carcinoma (HCC). The present study investigated the immunohistochemical expression of SIRT7, H3K18ac, and ELK4 in hepatocellular carcinoma. METHODS: A total of 278 HCC patients were enrolled in this study. Tissue microarray blocks were made from existing paraffin-embedded blocks. Immunohistochemical expressions of SIRT7, H3K18ac and ELK4 were scored and analyzed. RESULTS: High SIRT7 (p = .034), high H3K18ac (p = .001), and low ELK4 (p = .021) groups were associated with poor outcomes. Age < 65 years (p = .028), tumor size ≥ 5 cm (p = .001), presence of vascular emboli (p = .003), involvement of surgical margin (p = .001), and high American Joint Committee on Cancer stage (III&V) (p < .001) were correlated with worse prognoses. In multivariate analysis, H3K18ac (p = .001) and ELK4 (p = .015) were the significant independent prognostic factors. CONCLUSIONS: High SIRT7 expression with poor overall survival implies that deacetylation of H3K18ac contributes to progression of HCC. High H3K18ac expression with poor prognosis is predicted due to a compensation mechanism. In addition, high ELK4 expression with good prognosis suggests another role of ELK4 as a tumor suppressor beyond SIRT7's helper. In conclusion, we could assume that the H3K18ac deacetylation pathway is influenced by many other factors.