|
1
|
Mahjabeen I, Hussain MZ, Haq MFU, Mehmood A, Haris MS, Khan SA, Chaudhry A, Hakim F, Abbasi AZ, Kayani MA. Exploring the Role of Mitochondrial Sirtuin 3 Gene in Gastric Cancer Risk Based on SNP Analysis and LORD-Q Assay. Biochem Genet 2025:10.1007/s10528-025-11119-x. [PMID: 40293630 DOI: 10.1007/s10528-025-11119-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 04/22/2025] [Indexed: 04/30/2025]
Abstract
Mitochondrial sirtuin 3 (SIRT3) is a gene involved in key functions like acetylation, DNA repair, stress response, and tumorigenesis. Several studies have been published that showed the role of SIRT3 in various cancers. Still, few studies have been reported on the genetic and expression variation of the SIRT3 gene in gastric carcinogenesis. This study was designed to explore the involvement of the SIRT3 gene in gastric cancer. In this study, we used two study cohorts, cohort 1 contained 510 gastric cancer (GC) patients and an equal number of age and gender-matched controls. Cohort 2 included 220 GC tissue samples along with adjacent control tissues. Tetra Arms PCR was used to measure the frequency of three selected SNPs of the SIRT3 gene (rs28365927, rs11246029, and rs3817629) in cohort 1. Quantitative PCR and immunohistochemistry were performed to analyze the SIRT3 expression variation in cohort 2 GC patients. The superoxide dismutase (SOD), and 8-hydroxydeoxyguanosine (8-OHdG) levels were measured using ELISA, and DNA damage was measured using the LORD-Q assay. Statistical analysis showed the significant increased frequency of mutant allele of selected SNPs (rs28365927 (p < 0.0001); rs11246029 (p < 0.0001); and rs3817629 (p < 0.0001) in GC patients compared to controls. Expression analysis results showed significant downregulation of the SIRT3 gene at mRNA level (P < 0.001) and protein level (P < 0.001) in gastric tumor section vs control tissues. Multivariant Cox regression analysis showed that downregulated SIRT3 expression (p < 0.000001), H. pylori status (p < 0.0001), T-stage (p < 0.008), and N-stage (p < 0.001) act as prognostic markers in GC patients. ROC curve analysis showed the 90% and 100% specificity of the SIRT3 gene as a diagnostic marker in GC at the mRNA level and protein level, respectively. Significant increased oxidative stress (antioxidant enzyme level p < 0.0001; 8-OHdG level p < 0.0001) and lesion frequency/10 kb (p < 0.03) were indicated in the gastric tumor tissue sections vs controls. The result showed the tumor suppressor role of the SIRT3 gene in GC and was found linked with the surge in oxidative stress and damage in GC patients.
Collapse
Affiliation(s)
- Ishrat Mahjabeen
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan.
| | | | - Maria Fazal-Ul Haq
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Azhar Mehmood
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Muhammad Shahbaz Haris
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Shereen Ali Khan
- Department of Rheumatology, CMH Multan Institute of Medical Sciences, Multan, Pakistan
| | - Anum Chaudhry
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Farzana Hakim
- Department of Biochemistry, Foundation University Medical College, Islamabad, Pakistan
| | - Ayesha Zulfiqar Abbasi
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Mahmood Akhtar Kayani
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| |
Collapse
|
|
2
|
Yuan ML, Ren LH, Yu XC, Dong JW, Shi RH. SIRT3 Promotes the Development of Esophageal Squamous Cell Carcinoma by Regulating Hexokinase 2 through the AKT Signaling Pathway. Bull Exp Biol Med 2022; 174:81-88. [PMID: 36437337 DOI: 10.1007/s10517-022-05653-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Indexed: 11/29/2022]
Abstract
In the present study, we explored whether sirtuin-3 (SIRT3) regulates the proliferation and migration of esophageal squamous cell carcinoma (ESCC) and investigated the mechanisms underlying the oncogene role of SIRT3. siRNA was used to transfect Eca109 cells and downregulate SIRT3. The proliferation and migration of Eca109 cells were examined by the CCK-8 assay, colony formation assay, Transwell assay, and scratch test. Quantitative real-time PCR and Western blotting were used to detect SIRT3, hexokinase 2, AKT, and p-AKT in Eca109 cells. Functional assays showed that downregulation of SIRT3 could inhibit the proliferation and migration of ESCC cells. Reduced SIRT3 expression downregulated hexokinase 2 expression and inhibited AKT activation in ESCC. These results indicated that SIRT3 promote ESCC development and progression by regulating hexokinase 2 through the AKT signaling pathway. SIRT3 promote ESCC proliferation and migration by regulating HK-2 through the AKT signaling pathway.
Collapse
Affiliation(s)
- M L Yuan
- Department of Gastroenterology, Xuyi People's Hospital, Huaian, Jiangsu, China
| | - L H Ren
- Department of Gastroenterology, the Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu, China
| | - X C Yu
- Department of Gastroenterology, Xuyi People's Hospital, Huaian, Jiangsu, China
| | - J W Dong
- Department of Gastroenterology, Xuyi People's Hospital, Huaian, Jiangsu, China
| | - R H Shi
- Department of Gastroenterology, the Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu, China.
| |
Collapse
|
|
3
|
Otsuka R, Hayano K, Matsubara H. Role of sirtuins in esophageal cancer: Current status and future prospects. World J Gastrointest Oncol 2022; 14:794-807. [PMID: 35582109 PMCID: PMC9048530 DOI: 10.4251/wjgo.v14.i4.794] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/02/2022] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
Esophageal cancer (EC) is a malignant cancer that still has a poor prognosis, although its prognosis has been improving with the development of multidisciplinary treatment modalities such as surgery, chemotherapy and radiotherapy. Therefore, identifying specific molecular markers that can be served as biomarkers for the prognosis and treatment response of EC is highly desirable to aid in the personalization and improvement of the precision of medical treatment. Sirtuins are a family of nicotinamide adenine dinucleotide (NAD+)-dependent proteins consisting of seven members (SIRT1-7). These proteins have been reported to be involved in the regulation of a variety of biological functions including apoptosis, metabolism, stress response, senescence, differentiation and cell cycle progression. Given the variety of functions of sirtuins, they are speculated to be associated in some manner with cancer progression. However, while the role of sirtuins in cancer progression has been investigated over the past few years, their precise role remains difficult to characterize, as they have both cancer-promoting and cancer-suppressing properties, depending on the type of cancer. These conflicting characteristics make research into the nature of sirtuins all the more fascinating. However, the role of sirtuins in EC remains unclear due to the limited number of reports concerning sirtuins in EC. We herein review the current findings and future prospects of sirtuins in EC.
Collapse
Affiliation(s)
- Ryota Otsuka
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| | - Koichi Hayano
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| |
Collapse
|
|
4
|
Tao F, Gu C, Li N, Ying Y, Feng Y, Ni D, Zhang Q, Xiao Q. SIRT3 acts as a novel biomarker for the diagnosis of lung cancer: A retrospective study. Medicine (Baltimore) 2021; 100:e26580. [PMID: 34232204 PMCID: PMC8270582 DOI: 10.1097/md.0000000000026580] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 06/10/2021] [Indexed: 01/04/2023] Open
Abstract
Lung cancer (LC) is a prevalent malignancy worldwide with increased morbidity and mortality. Mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-3 (SIRT3) has been reported to be involved in tumorigenesis. In this retrospective study, we measured the expression and diagnostic value of SIRT3 in LC patients.Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure serum SIRT3 mRNA level in 150 LC patients and 52 healthy volunteers. SIRT3 protein level was detected using western blot for 84 pairs of LC and adjacent normal tissues. The association of SIRT3 mRNA level with clinical parameters of LC patients was estimated via chi-square test. Receiver operating characteristic curve (ROC) was plotted to evaluate the diagnostic performance of serum SIRT3 in LC patients.SIRT3 mRNA and protein levels were significantly decreased in LC tissues and serum samples, compared with corresponding controls (P < .05). Moreover, the expression of SIRT3 mRNA was negatively associated with tumor size (P = .002), tumor node metastasis stage (P < .001), and metastasis (P < .001). ROC curve demonstrated that serum SIRT3 could distinguish LC patients from healthy individuals, with an area under the curve of 0.918. The optimal cutoff value was 3.12, reaching a sensitivity of 86.4%, and a specificity of 94%.SIRT3 expression is significantly down-regulated in LC serum and tissues. SIRT3 may be employed as a promising biomarker in the early diagnosis of LC.
Collapse
|
|
5
|
Jaiswal A, Xudong Z, Zhenyu J, Saretzki G. Mitochondrial sirtuins in stem cells and cancer. FEBS J 2021; 289:3393-3415. [PMID: 33866670 DOI: 10.1111/febs.15879] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 04/13/2021] [Indexed: 12/15/2022]
Abstract
The mammalian sirtuin family consists of seven proteins, three of which (SIRT3, SIRT4, and SIRT5) localise specifically within mitochondria and preserve mitochondrial function and homeostasis. Mitochondrial sirtuins are involved in diverse functions such as deacetylation, ADP-ribosylation, demalonylation and desuccinylation, thus affecting various aspects of cell fate. Intriguingly, mitochondrial sirtuins are able to manage these delicate processes with accuracy mediated by crosstalk between the nucleus and mitochondria. Previous studies have provided ample information about their substrates and targets, whereas less is known about their role in cancer and stem cells. Here, we review and discuss recent advances in our understanding of the structural and functional properties of mitochondrial sirtuins, including their targets in cancer and stem cells. These advances could help to improve the understanding of their interplay with signalling cascades and pathways, leading to new avenues for developing novel drugs for sirtuin-related disease treatments. We also highlight the complex network of mitochondrial sirtuins in cancer and stem cells, which may be important in deciphering the molecular mechanism for their activation and inhibition.
Collapse
Affiliation(s)
- Amit Jaiswal
- Institute of Ageing Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.,Faculty of Biological Sciences, Friedrich Schiller University, Jena, Germany
| | - Zhu Xudong
- Faculty of Biological Sciences, Friedrich Schiller University, Jena, Germany
| | - Ju Zhenyu
- Institute of Ageing Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.,Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Ageing and Regenerative Medicine, Jinan University, Guangzhou, Guangdong, China
| | - Gabriele Saretzki
- Campus for Ageing and Vitality, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| |
Collapse
|
|
6
|
Epigenetic Alterations in Oesophageal Cancer: Expression and Role of the Involved Enzymes. Int J Mol Sci 2020; 21:ijms21103522. [PMID: 32429269 PMCID: PMC7278932 DOI: 10.3390/ijms21103522] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 12/25/2022] Open
Abstract
Oesophageal cancer is a life-threatening disease, accounting for high mortality rates. The poor prognosis of this malignancy is mostly due to late diagnosis and lack of effective therapies for advanced disease. Epigenetic alterations may constitute novel and attractive therapeutic targets, owing to their ubiquity in cancer and their reversible nature. Herein, we offer an overview of the most important studies which compared differences in expression of enzymes that mediate epigenetic alterations between oesophageal cancer and normal mucosa, as well as in vitro data addressing the role of these genes/proteins in oesophageal cancer. Furthermore, The Cancer Genome Atlas database was interrogated for the correlation between expression of these epigenetic markers and standard clinicopathological features. We concluded that most epigenetic players studied thus far are overexpressed in tumours compared to normal tissue. Furthermore, functional assays suggest an oncogenic role for most of those enzymes, supporting their potential as therapeutic targets in oesophageal cancer.
Collapse
|
|
7
|
SIRT3 promotes the invasion and metastasis of cervical cancer cells by regulating fatty acid synthase. Mol Cell Biochem 2019; 464:11-20. [DOI: 10.1007/s11010-019-03644-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 10/23/2019] [Indexed: 12/15/2022]
|
|
8
|
Li J, Yue H, Yu H, Lu X, Xue X. Development and validation of SIRT3-related nomogram predictive of overall survival in patients with serous ovarian cancer. J Ovarian Res 2019; 12:47. [PMID: 31113446 PMCID: PMC6530022 DOI: 10.1186/s13048-019-0524-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 05/13/2019] [Indexed: 01/10/2023] Open
Abstract
Objective Our aim is to analyzed the expression pattern of sirtuin(SIRT) superfamily and evaluated their prognostic values in serous ovarian cancer patients. Methods We first analyzed the differential expression of SIRT members among fallopian tube epithelium (FTE), primary serous ovarian cancers/tubal cancers (PSOCs/PSTCs), and omental metastases using GSE10971 and GSE30587 datasets. The prognostic values of SIRT members were evaluated using TCGA and GSE9891 dataset. Results SIRT3 and SIRT5 expression were significantly decreased and increased in PSOCs/PSTCs compared with that in normal counterparts, respectively. SIRT6 and SIRT7 were overexpressed in ometal metastases compared with corresponding primary counterparts. With respect to recurrence free survival, however, SIRT7 overexpression was correlated with better prognosis. A similar trend was observed by multivariable analysis. Regarding overall survival (OS), increased expression of SIRT3, SIRT5, and SIRT7 were associated with better survival by univariable analysis. Subsequent multivariable analysis showed that SIRT3 remained an independent favorable prognostic factor for OS. The SIRT3-related nomogram illustrated age at initial diagnosis as sharing the largest contribution to OS, followed by SIRT3 expression and FIGO stage. The C-index for OS prediction was 0.65 (95%CI, 0.61–0.69) in training cohort (TCGA dataset) and 0.65 (95%CI, 0.59–0.71) in validation cohort (GSE9891 dataset), respectively. The calibration plots showed optimal agreement between the prediction by SIRT3-related nomogram and actual observation for 1-, 3-, and 5-year OS probability. Conclusion In conclusion, SIRT3 was an independent favorable prognostic factor for OS in serous ovarian cancer, and added prognostic value to the traditional clinicopathological factors used to evaluate patients’ prognosis.
Collapse
Affiliation(s)
- Jun Li
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No.419, Fangxie Road, Shanghai, 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China
| | - Huiran Yue
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No.419, Fangxie Road, Shanghai, 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China
| | - Hailin Yu
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No.419, Fangxie Road, Shanghai, 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China
| | - Xin Lu
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No.419, Fangxie Road, Shanghai, 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China
| | - Xiaohong Xue
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No.419, Fangxie Road, Shanghai, 200011, China. .,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China.
| |
Collapse
|
|
9
|
Zhou Y, Cheng S, Chen S, Zhao Y. Prognostic and clinicopathological value of SIRT3 expression in various cancers: a systematic review and meta-analysis. Onco Targets Ther 2018; 11:2157-2167. [PMID: 29713184 PMCID: PMC5907887 DOI: 10.2147/ott.s157836] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background Several studies have explored the prognostic value of sirtuin 3 (SIRT3) in various cancers, but obtained inconsistent results. The current systematic review and meta-analysis was conducted to investigate the association between SIRT3 expression and prognosis in various cancers. Methods PubMed, Embase, Web of Science and the Cochrane Library were comprehensively retrieved by the end of September 29, 2017. All the relevant studies were checked and included in the meta-analysis if they met the inclusion criteria. Results A total of 17 studies involving 2,865 patients were included in the systematic review and meta-analysis. The results indicated that SIRT3 expression was not significantly associated with overall survival (OS) (hazard ratio [HR]=0.87, 95% CI=0.59–1.29, P=0.50) and disease-free survival (HR=0.87, 95% CI=0.57–1.31, P=0.50) in total various cancers. However, significant relationship between SIRT3 expression and OS in specific cancers was detected, including chronic lymphocytic leukemia (CLL) (HR=0.48, 95% CI=0.26–0.89, P=0.019), hepatocellular carcinoma (HCC) (HR=0.56, 95% CI=0.42–0.74, P<0.001), pancreatic carcinoma (PC) (HR=0.55, 95% CI=0.30–1.00, P=0.049), renal cell carcinoma (RCC) (HR=0.13, 95% CI=0.02–0.98, P=0.048), breast cancer (BC) (HR=2.53, 95% CI=1.83–3.67, P<0.001), colon cancer (CC) (HR=1.87, 95% CI=1.12–3.26, P=0.022) and non-small-cell lung cancer (NSCLC) (HR=2.20, 95% CI=1.38–3.50, P=0.001). Moreover, SIRT3 expression was obviously associated with tumor size (odds ratio [OR]=1.41, 95% CI=1.02–1.94, P=0.04), tumor differentiation (OR=1.52, 95% CI=1.08–2.16, P=0.02) and clinical stage (OR=2.07, 95% CI=1.23–3.46, P=0.01) in HCC. Conclusion SIRT3 was distinctly related to the OS in specific cancers. SIRT3 was an unfavorable prognostic factor in BC, CC and NSCLC; however, it was also a favorable prognostic factor in CLL, HCC, PC and RCC, especially in HCC.
Collapse
Affiliation(s)
- Yongping Zhou
- Department of Hepatobiliary, Wuxi Second Hospital, Nanjing Medical University, Wuxi, People's Republic of China
| | - Sijin Cheng
- Tongji University School of Medicine, Shanghai, China
| | - Sinuo Chen
- Tongji University School of Medicine, Shanghai, China
| | - Yongzhao Zhao
- Department of Hepatobiliary, Wuxi Second Hospital, Nanjing Medical University, Wuxi, People's Republic of China.,Tongji University School of Medicine, Shanghai, China
| |
Collapse
|
|
10
|
Tao NN, Zhou HZ, Tang H, Cai XF, Zhang WL, Ren JH, Zhou L, Chen X, Chen K, Li WY, Liu B, Yang QX, Cheng ST, Huang LX, Huang AL, Chen J. Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway. Oncotarget 2018; 7:50117-50130. [PMID: 27367026 PMCID: PMC5226572 DOI: 10.18632/oncotarget.10319] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Accepted: 06/16/2016] [Indexed: 12/22/2022] Open
Abstract
SIRT3, a class III histone deacetylase, has been implicated in various cancers as a novel therapeutic target. In hepatocellular carcinoma (HCC), we previously reported that SIRT3 induced cell apoptosis by regulating GSK-3β/Bax signaling pathway. Downregulation of SIRT3 in HCC cells facilitates tumor cell survival. In this study, we found that chemotherapeutic agents (doxorubicin, cisplatin and epirubicin) and sorafenib treatment downregulated SIRT3 mRNA and protein levels in three HCC cell lines. MTS assay found that SIRT3 overexpression sensitized liver cancer cells to chemotherapeutic agents and sorafenib in SMMC-7721, Huh-7 and PLC/PRF/5 cell lines. Moreover, SIRT3 overexpression promoted chemotherapeutic agents-induced or sorafenib-induced apoptosis as evidenced by flow cytometry, enhanced PARP cleavage and enhanced Caspase-9 cleavage in three HCC cells. In contrast, SIRT3 silencing increased drug resistance of HCC cells to chemotherapeutic agents. Mechanistic study found that SIRT3 downregulated the mRNA and protein levels of glutathione S-transferase pi 1 (GSTP1), which is a member of phase II detoxification enzymes families involved in metabolizing for chemotherapeutic agents. Moreover, SIRT3 decreased the amount of GSTP1 that was associated with JNK, which finally contributed the activation of JNK activity and activation of downstream target c-Jun and Bim. Importantly, GSTP1 overexpression or JNK inhibitor abolished SIRT3-induced apoptosis in HCC cells exposed to chemotherapeutic agents. Finally, there was a negative correlation between SIRT3 expression and GSTP1 expression in human HCC tissues. Together, our findings revealed SIRT3 could enhance the drug sensitivity of HCC cells to an array of chemotherapeutic agents. SIRT3 may serve as a potential target for improving the chemosensitivity of HCC patients.
Collapse
Affiliation(s)
- Na-Na Tao
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hong-Zhong Zhou
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hua Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Zhejiang, China
| | - Xue-Fei Cai
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Wen-Lu Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ji-Hua Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Li Zhou
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Xiang Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ke Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Wan-Yu Li
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Bo Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Qiu-Xia Yang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Sheng-Tao Cheng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Li-Xia Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ai-Long Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Zhejiang, China
| | - Juan Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
11
|
Huang S, Chen X, Zheng J, Huang Y, Song L, Yin Y, Xiong J. Low SIRT3 expression contributes to tumor progression, development and poor prognosis in human pancreatic carcinoma. Pathol Res Pract 2017; 213:1419-1423. [PMID: 28867266 DOI: 10.1016/j.prp.2017.07.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 06/25/2017] [Accepted: 07/19/2017] [Indexed: 01/21/2023]
Abstract
SIRT3, an important mitochondrial protein, may act as either an oncogene or tumor suppressor depending on the tumor-type. The aim of this study was to investigate the expression of SIRT3 in pancreatic carcinoma (PC) and its clinical association in PC patients. Immunohistochemistry was adopted to investigate the expression of SIRT3 in cancer and corrresponding adjacent non-cancer tissues across 79 patients with PC. The log-rank test and Cox hazard model were used to estimate the relationship between SIRT3 expression and prognosis. The staining results revealed that SIRT3 negative expression was more common in cancer tissues than in adjacent non-cancer tissues (P<0.001). Chi-square tests indicated that the expression of SIRT3 correlated with T status (p<0.001) and tumor stage (p=0.013). Kaplan-Meier analysis showed that negative SIRT3 expression is linked to a poor prognosis in PC patients. Multivariate analysis identified SIRT3 expression as an independent predictor for PC outcome both in the whole cohort and several subgroups of PC patients. Our results indicate that down-regulated SIRT3 may contribute to tumor progression and gloomy prognosis in PC patients and may sever as a novel prognostic marker.
Collapse
Affiliation(s)
- Shanshan Huang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Jiangxi, China
| | - Xiong Chen
- Department of Medical Oncology, Fuzhou General Hospital of Nanjing Military Command, Fuzong Clinical College of Fujian Medical University, Fujian, China
| | - Jiawei Zheng
- Department of Medical Oncology, Fuzhou General Hospital of Nanjing Military Command, Fuzong Clinical College of Fujian Medical University, Fujian, China
| | - Yufang Huang
- Department of Medical Oncology, Fuzhou General Hospital of Nanjing Military Command, Fuzong Clinical College of Fujian Medical University, Fujian, China
| | - Li Song
- Department of Medical Oncology, Fuzhou General Hospital of Nanjing Military Command, Fuzong Clinical College of Fujian Medical University, Fujian, China
| | - Yin Yin
- Department of Medical Oncology, Fuzhou General Hospital of Nanjing Military Command, Medical College Xiamen University, Xiamen, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Jiangxi, China.
| |
Collapse
|
|
12
|
Jablonski RP, Kim SJ, Cheresh P, Williams DB, Morales-Nebreda L, Cheng Y, Yeldandi A, Bhorade S, Pardo A, Selman M, Ridge K, Gius D, Budinger GRS, Kamp DW. SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis. FASEB J 2017; 31:2520-2532. [PMID: 28258190 DOI: 10.1096/fj.201601077r] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 02/07/2017] [Indexed: 01/28/2023]
Abstract
Alveolar epithelial cell (AEC) mitochondrial dysfunction and apoptosis are important in idiopathic pulmonary fibrosis and asbestosis. Sirtuin 3 (SIRT3) detoxifies mitochondrial reactive oxygen species, in part, by deacetylating manganese superoxide dismutase (MnSOD) and mitochondrial 8-oxoguanine DNA glycosylase. We reasoned that SIRT3 deficiency occurs in fibrotic lungs and thereby augments AEC mtDNA damage and apoptosis. Human lungs were assessed by using immunohistochemistry for SIRT3 activity via acetylated MnSODK68 Murine AEC SIRT3 and cleaved caspase-9 (CC-9) expression were assayed by immunoblotting with or without SIRT3 enforced expression or silencing. mtDNA damage was measured by using quantitative PCR and apoptosis via ELISA. Pulmonary fibrosis after asbestos or bleomycin exposure was evaluated in 129SJ/wild-type and SIRT3-knockout mice (Sirt3-/- ) by using fibrosis scoring and lung collagen levels. Idiopathic pulmonary fibrosis lung alveolar type II cells have increased MnSODK68 acetylation compared with controls. Asbestos and H2O2 diminished AEC SIRT3 protein expression and increased mitochondrial protein acetylation, including MnSODK68 SIRT3 enforced expression reduced oxidant-induced AEC OGG1K338/341 acetylation, mtDNA damage, and apoptosis, whereas SIRT3 silencing promoted these effects. Asbestos- or bleomycin-induced lung fibrosis, AEC mtDNA damage, and apoptosis in wild-type mice were amplified in Sirt3-/- animals. These data suggest a novel role for SIRT3 deficiency in mediating AEC mtDNA damage, apoptosis, and lung fibrosis.-Jablonski, R. P., Kim, S.-J., Cheresh, P., Williams, D. B., Morales-Nebreda, L., Cheng, Y., Yeldandi, A., Bhorade, S., Pardo, A., Selman, M., Ridge, K., Gius, D., Budinger, G. R. S., Kamp, D. W. SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis.
Collapse
Affiliation(s)
- Renea P Jablonski
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Seok-Jo Kim
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Paul Cheresh
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - David B Williams
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Luisa Morales-Nebreda
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Yuan Cheng
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Anjana Yeldandi
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Sangeeta Bhorade
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Annie Pardo
- Facultad de Ciencias, Universidad Nacional Autónoma de México, México City, Mexico
| | - Moises Selman
- Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, México City, Mexico
| | - Karen Ridge
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - David Gius
- Department of Radiation Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - G R Scott Budinger
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - David W Kamp
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA; .,Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| |
Collapse
|
|
13
|
Ansari A, Rahman MS, Saha SK, Saikot FK, Deep A, Kim KH. Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging Cell 2017; 16:4-16. [PMID: 27686535 PMCID: PMC5242307 DOI: 10.1111/acel.12538] [Citation(s) in RCA: 224] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/22/2016] [Indexed: 12/11/2022] Open
Abstract
In mammals, seven members of the sirtuin protein family known as class III histone deacetylase have been identified for their characteristic features. These distinguished characteristics include the tissues where they are distributed or located, enzymatic activities, molecular functions, and involvement in diseases. Among the sirtuin members, SIRT3 has received much attention for its role in cancer genetics, aging, neurodegenerative disease, and stress resistance. SIRT3 controls energy demand during stress conditions such as fasting and exercise as well as metabolism through the deacetylation and acetylation of mitochondrial enzymes. SIRT3 is well known for its ability to eliminate reactive oxygen species and to prevent the development of cancerous cells or apoptosis. This review article provides a comprehensive review on numerous (noteworthy) molecular functions of SIRT3 and its effect on cancer cells and various diseases including Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease.
Collapse
Affiliation(s)
- Aneesa Ansari
- Department of Genetic Engineering and Biotechnology; Jessore University of Science and Technology; Jessore 7408 Bangladesh
| | - Md. Shahedur Rahman
- Department of Genetic Engineering and Biotechnology; Jessore University of Science and Technology; Jessore 7408 Bangladesh
| | - Subbroto K. Saha
- Department of Stem Cell and Regenerative Biology; Konkuk University; 120 Neungdong-Ro Seoul 05029 Korea
| | - Forhad K. Saikot
- Department of Genetic Engineering and Biotechnology; Jessore University of Science and Technology; Jessore 7408 Bangladesh
| | - Akash Deep
- Central Scientific Instruments Organisation (CSIR-CSIO); Sector 30 C Chandigarh 160030 India
| | - Ki-Hyun Kim
- Department of Civil & Environmental Engineering; Hanyang University; 222 Wangsimni-Ro Seoul 04763 Korea
| |
Collapse
|
|
14
|
Gertz M, Steegborn C. Using mitochondrial sirtuins as drug targets: disease implications and available compounds. Cell Mol Life Sci 2016; 73:2871-96. [PMID: 27007507 PMCID: PMC11108305 DOI: 10.1007/s00018-016-2180-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 02/15/2016] [Accepted: 03/11/2016] [Indexed: 02/06/2023]
Abstract
Sirtuins are an evolutionary conserved family of NAD(+)-dependent protein lysine deacylases. Mammals have seven Sirtuin isoforms, Sirt1-7. They contribute to regulation of metabolism, stress responses, and aging processes, and are considered therapeutic targets for metabolic and aging-related diseases. While initial studies were focused on Sirt1 and 2, recent progress on the mitochondrial Sirtuins Sirt3, 4, and 5 has stimulated research and drug development for these isoforms. Here we review the roles of Sirtuins in regulating mitochondrial functions, with a focus on the mitochondrially located isoforms, and on their contributions to disease pathologies. We further summarize the compounds available for modulating the activity of these Sirtuins, again with a focus on mitochondrial isoforms, and we describe recent results important for the further improvement of compounds. This overview illustrates the potential of mitochondrial Sirtuins as drug targets and summarizes the status, progress, and challenges in developing small molecule compounds modulating their activity.
Collapse
Affiliation(s)
- Melanie Gertz
- Department of Biochemistry, University of Bayreuth, Universitätsstr. 30, 95447, Bayreuth, Germany
- Bayer Pharma AG, Apratherweg 18a, 42096, Wuppertal, Germany
| | - Clemens Steegborn
- Department of Biochemistry, University of Bayreuth, Universitätsstr. 30, 95447, Bayreuth, Germany.
| |
Collapse
|
|
15
|
George J, Ahmad N. Mitochondrial Sirtuins in Cancer: Emerging Roles and Therapeutic Potential. Cancer Res 2016; 76:2500-6. [PMID: 27197261 DOI: 10.1158/0008-5472.can-15-2733] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 02/17/2016] [Indexed: 01/22/2023]
Abstract
The past few decades have witnessed a furious attention of scientific community toward identifying novel molecular factors and targets that could be exploited for drug development for cancer management. One such factor is the sirtuin (SIRT) family of nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylases. The role of SIRTs in cancer is extremely complex, with dichotomous functions depending on cell contexts. Mammalian SIRTs (SIRT1-7) differ in their cellular localization and biologic functions. Among these, SIRT -3, -4, and -5 are located in the mitochondria and are being carefully investigated. These mitochondrial SIRTs (mtSIRT) regulate multiple cellular and physiologic processes, including cell cycle, gene expression, cell viability, stress response, metabolism, and energy homeostasis. Recent research suggests that mtSIRTs influence tumors by regulating the metabolic state of the cell. Although the research on the role of mtSIRTs in cancer is still in its infancy, studies have suggested tumor suppressor as well as tumor promoter roles for them. This review is focused on discussing up-to-date information about the roles and functional relevance of mtSIRTs (SIRT -3, -4, -5) in cancers. We have also provided a critical discussion and our perspective on their dual roles, as tumor promoter versus tumor suppressor, in cancer. Cancer Res; 76(9); 2500-6. ©2016 AACR.
Collapse
Affiliation(s)
- Jasmine George
- Department of Dermatology, University of Wisconsin, Madison, Wisconsin
| | - Nihal Ahmad
- Department of Dermatology, University of Wisconsin, Madison, Wisconsin. William S. Middleton VA Medical Center, Madison, Wisconsin.
| |
Collapse
|
|
16
|
Yu FY, Xu Q, Wu DD, Lau ATY, Xu YM. The Prognostic and Clinicopathological Roles of Sirtuin-3 in Various Cancers. PLoS One 2016; 11:e0159801. [PMID: 27483432 PMCID: PMC4970700 DOI: 10.1371/journal.pone.0159801] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 07/10/2016] [Indexed: 02/05/2023] Open
Abstract
Sirtuin-3 (SIRT3) is a major mitochondrial NAD(+)-dependent deacetylase and plays a key role in the progression and development of human cancers. Although the prognostic and clinicopathological features of SIRT3 expression in various cancers have been investigated by different research groups, however, inconsistent and opposing results can be observed. In this study, we therefore performed a meta-analysis to evaluate the significance of SIRT3 expression in various cancers. Systematic literature searching was performed in PubMed, Embase, China National Knowledge Infrastructure, and Wanfang Data up to November 2015. Total effect analyses and subgroup analyses were performed to evaluate the relationship between SIRT3 expression and overall survival, cancer/non-cancer tissues, lymph node metastasis, pathological differentiation, tumor node metastasis (TNM) stage, tumor size, and gender, in various cancer patients. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to clarify the risk or hazard association. A total of 14 studies comprising 2165 cancer patients were included to assess the association between SIRT3 immunohistochemical expression and overall survival or clinicopathological characteristics. SIRT3 expression was significantly associated with overall survival in gastric cancer (HR = 0.62, 95% CI = 0.43-0.89, P = 0.009) and hepatocellular carcinoma patients (HR = 0.56, 95% CI = 0.42-0.74, P<0.0001), cancer/non-cancer tissues in hepatocellular carcinoma patients (OR = 0.04, 95% CI = 0.01-0.16, P<0.0001), lymph node metastasis in breast cancer patients (OR = 2.20, 95% CI = 1.49-3.26, P<0.0001), and also pathological differentiation in hepatocellular carcinoma patients (OR = 0.69, 95% CI = 0.48-0.98, P = 0.04) and gastric cancer patients (OR = 0.33, 95% CI = 0.21-0.50, P<0.00001), by subgroup analyses. Furthermore, SIRT3 expression was significantly associated with pathological differentiation in total effect analysis (OR = 0.46, 95% CI = 0.29-0.74, P = 0.001). No detectable relation between SIRT3 expression and other clinicopathological parameters were found. This meta-analysis indicates that SIRT3 expression level is associated with prognostic and clinical features in specific cancers.
Collapse
Affiliation(s)
- Fei-Yuan Yu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, 515041, P. R. China
| | - Qian Xu
- Department of Pathology, Shantou University Medical College, Shantou, Guangdong, 515041, P. R. China
| | - Dan-Dan Wu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, 515041, P. R. China
| | - Andy T. Y. Lau
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, 515041, P. R. China
- * E-mail: (YMX); (ATYL)
| | - Yan-Ming Xu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, 515041, P. R. China
- * E-mail: (YMX); (ATYL)
| |
Collapse
|
|
17
|
George J, Nihal M, Singh CK, Zhong W, Liu X, Ahmad N. Pro-Proliferative Function of Mitochondrial Sirtuin Deacetylase SIRT3 in Human Melanoma. J Invest Dermatol 2015; 136:809-818. [PMID: 26743598 DOI: 10.1016/j.jid.2015.12.026] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Revised: 11/30/2015] [Accepted: 12/07/2015] [Indexed: 11/28/2022]
Abstract
Melanoma, the most aggressive form of skin cancer, is often fatal if not treated early. Therefore, novel target-based strategies are required to combat this neoplasm. The objective of this study was to determine the role and functional significance of the mitochondrial sirtuin 3 (SIRT3) in melanoma. We found that compared with normal primary and immortalized human melanocytes, SIRT3 is significantly overexpressed in multiple human melanoma cells at mRNA and protein levels. Further, employing human tissue microarray, we found that SIRT3 is significantly upregulated in clinical melanoma tissues, compared with melanocytic nevi tissues. Furthermore, a short hairpin RNA-mediated knockdown of SIRT3 in human melanoma cells resulted in (i) a decrease in cellular proliferation, colony formation, and cellular migration; (ii) induction of senescence as shown by an increase in senescence-associated beta-galactosidase activity and formation of senescence-associated heterochromatin foci as well as an increase in mRNA and protein levels of p16(INK4a) and p21(Waf1); (iii) G1-phase arrest of the cell cycle; and (iv) decreases in mRNA and protein levels of cyclins (D1, E1) and cyclin-dependent kinases (2, 4, and 6). Conversely, forced exogenous overexpression of SIRT3 promoted an increase in proliferative potential of Hs294T melanoma cells and normal immortalized Mel-ST melanocytes. Finally, we found that SIRT3 knockdown significantly inhibited tumorigenesis in a xenograft model in vivo. To our knowledge, this is the first study supporting the pro-proliferative function of SIRT3 in melanoma.
Collapse
Affiliation(s)
- Jasmine George
- Department of Dermatology, University of Wisconsin, Madison, Wisconsin, USA
| | - Minakshi Nihal
- Department of Dermatology, University of Wisconsin, Madison, Wisconsin, USA
| | - Chandra K Singh
- Department of Dermatology, University of Wisconsin, Madison, Wisconsin, USA
| | - Weixiong Zhong
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, USA
| | - Xiaoqi Liu
- Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA
| | - Nihal Ahmad
- Department of Dermatology, University of Wisconsin, Madison, Wisconsin, USA; William S. Middleton VA Medical Center, Madison, Wisconsin, USA.
| |
Collapse
|
|
18
|
Yu W, Denu RA, Krautkramer KA, Grindle KM, Yang DT, Asimakopoulos F, Hematti P, Denu JM. Loss of SIRT3 Provides Growth Advantage for B Cell Malignancies. J Biol Chem 2015; 291:3268-79. [PMID: 26631723 DOI: 10.1074/jbc.m115.702076] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Indexed: 12/16/2022] Open
Abstract
B cell malignancies comprise a diverse group of cancers that proliferate in lymph nodes, bone marrow, and peripheral blood. SIRT3 (sirtuin 3) is the major deacetylase within the mitochondrial matrix that promotes aerobic metabolism and controls reactive oxygen species (ROS) by deacetylating and activating isocitrate dehydrogenase 2 (IDH2) and superoxide dismutase 2 (SOD2). There is controversy as to whether SIRT3 acts as an oncogene or a tumor suppressor, and here we investigated its role in B cell malignancies. In mantle cell lymphoma patient samples, we found that lower SIRT3 protein expression was associated with worse overall survival. Further, SIRT3 protein expression was reduced in chronic lymphocytic leukemia primary samples and malignant B cell lines compared to primary B cells from healthy donors. This lower level of expression correlated with hyperacetylation of IDH2 and SOD2 mitochondrial proteins, lowered enzymatic activities, and higher ROS levels. Overexpression of SIRT3 decreased proliferation and diminished the Warburg-like phenotype in SIRT3-deficient cell lines, and this effect is largely dependent on deacetylation of IDH2 and SOD2. Lastly, depletion of SIRT3 from malignant B cell lines resulted in greater susceptibility to treatment with an ROS scavenger but did not result in greater sensitivity to inhibition of the hypoxia-inducible factor-1α pathway, suggesting that loss of SIRT3 increases proliferation via ROS-dependent but hypoxia-inducible factor-1α-independent mechanisms. Our study suggests that SIRT3 acts as a tumor suppressor in B cell malignancies, and activating the SIRT3 pathway might represent a novel therapeutic approach for treating B cell malignancies.
Collapse
Affiliation(s)
- Wei Yu
- From the Wisconsin Institute for Discovery and the Department of Biomolecular Chemistry
| | - Ryan A Denu
- the Medical Scientist Training Program, and the Departments of Medicine and
| | - Kimberly A Krautkramer
- From the Wisconsin Institute for Discovery and the Department of Biomolecular Chemistry, the Medical Scientist Training Program, and
| | | | - David T Yang
- Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705 and
| | - Fotis Asimakopoulos
- the Departments of Medicine and the University of Wisconsin Carbone Cancer Center, Madison, Wisconsin 53792
| | - Peiman Hematti
- the Departments of Medicine and the University of Wisconsin Carbone Cancer Center, Madison, Wisconsin 53792
| | - John M Denu
- From the Wisconsin Institute for Discovery and the Department of Biomolecular Chemistry, the University of Wisconsin Carbone Cancer Center, Madison, Wisconsin 53792
| |
Collapse
|
|
19
|
Biomolecular bases of the senescence process and cancer. A new approach to oncological treatment linked to ageing. Ageing Res Rev 2015; 23:125-38. [PMID: 25847820 DOI: 10.1016/j.arr.2015.03.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 03/30/2015] [Indexed: 01/07/2023]
Abstract
Human ageing is associated with a gradual decline in the physiological functions of the body at multiple levels and it is a key risk factor for many diseases, including cancer. Ageing process is intimately related to widespread cellular senescence, characterised by an irreversible loss of proliferative capacity and altered functioning associated with telomere attrition, accumulation of DNA damage and compromised mitochondrial and metabolic function. Tumour and senescent cells may be generated in response to the same stimuli, where either cellular senescence or transformation would constitute two opposite outcomes of the same degenerative process. This paper aims to review the state of knowledge on the biomolecular relationship between cellular senescence, ageing and cancer. Importantly, many of the cell signalling pathways that are found to be altered during both cellular senescence and tumourigenesis are regulated through shared epigenetic mechanisms and, therefore, they are potentially reversible. MicroRNAs are emerging as pivotal players linking ageing and cancer. These small RNA molecules have generated great interest from the point of view of future clinical therapy for cancer because successful experimental results have been obtained in animal models. Micro-RNA therapies for cancer are already being tested in clinical phase trials. These findings have potential importance in cancer treatment in aged people although further research-based knowledge is needed to convert them into an effective molecular therapies for cancer linked to ageing.
Collapse
|
|
20
|
Vatrinet R, Iommarini L, Kurelac I, De Luise M, Gasparre G, Porcelli AM. Targeting respiratory complex I to prevent the Warburg effect. Int J Biochem Cell Biol 2015; 63:41-5. [PMID: 25668477 DOI: 10.1016/j.biocel.2015.01.017] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Revised: 01/15/2015] [Accepted: 01/29/2015] [Indexed: 12/20/2022]
Abstract
In the last 10 years, studies of energetic metabolism in different tumors clearly indicate that the definition of Warburg effect, i.e. the glycolytic shift cells undergo upon transformation, ought to be revisited considering the metabolic plasticity of cancer cells. In fact, recent findings show that the shift from glycolysis to re-established oxidative metabolism is required for certain steps of tumor progression, suggesting that mitochondrial function and, in particular, respiratory complex I are crucial for metabolic and hypoxic adaptation. Based on these evidences, complex I can be considered a lethality target for potential anticancer strategies. In conclusion, in this mini review we summarize and discuss why it is not paradoxical to develop pharmacological and genome editing approaches to target complex I as novel adjuvant therapies for cancer treatment. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies.
Collapse
Affiliation(s)
- Renaud Vatrinet
- Dipartimento di Farmacia e Biotecnologie (FABIT), Università di Bologna, via Irnerio 42, 40126 Bologna, Italy; Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), U.O. Genetica Medica, Pol. Universitario S. Orsola-Malpighi, Università di Bologna, via Massarenti 9, 40138 Bologna, Italy
| | - Luisa Iommarini
- Dipartimento di Farmacia e Biotecnologie (FABIT), Università di Bologna, via Irnerio 42, 40126 Bologna, Italy
| | - Ivana Kurelac
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), U.O. Genetica Medica, Pol. Universitario S. Orsola-Malpighi, Università di Bologna, via Massarenti 9, 40138 Bologna, Italy
| | - Monica De Luise
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), U.O. Genetica Medica, Pol. Universitario S. Orsola-Malpighi, Università di Bologna, via Massarenti 9, 40138 Bologna, Italy
| | - Giuseppe Gasparre
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), U.O. Genetica Medica, Pol. Universitario S. Orsola-Malpighi, Università di Bologna, via Massarenti 9, 40138 Bologna, Italy
| | - Anna Maria Porcelli
- Dipartimento di Farmacia e Biotecnologie (FABIT), Università di Bologna, via Irnerio 42, 40126 Bologna, Italy; Centro Interdipartimentale di Ricerca Industriale Scienze della Vita e Tecnologie per la Salute, Università di Bologna, 40100 Bologna, Italy.
| |
Collapse
|
|
21
|
Involved field irradiation for the treatment of esophageal cancer: Is it better than elective nodal irradiation? Cancer Lett 2015; 357:69-74. [DOI: 10.1016/j.canlet.2014.11.045] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 11/19/2014] [Accepted: 11/19/2014] [Indexed: 12/25/2022]
|