SIRT3 is correlated with the malignancy of non-small cell lung cancer

Xiong,Yanlu; Wang,Mingxing; Zhao,Jinbo; Wang,Lei; Li,Xiaofei; Zhang,Zhipei; Jia,Lintao; Han,Yong

doi:10.3892/ijo.2017.3868

SIRT3 is correlated with the malignancy of non-small cell lung cancer

Authors:
- Yanlu Xiong
- Mingxing Wang
- Jinbo Zhao
- Lei Wang
- Xiaofei Li
- Zhipei Zhang
- Lintao Jia
- Yong Han
View Affiliations

Affiliations: Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China, State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
Published online on: February 2, 2017 https://doi.org/10.3892/ijo.2017.3868
Pages: 903-910

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The mitochondrial deacetylase SIRT3 plays a pivotal role in the initiation and the progression of certain cancers acting as an oncogene. However, in others it acts anti-oncogenically. Its conflicting action is possibly due to the different key proteins it modifies depending on the context of active intracellular signaling pathways in different cancers. SIRT3 is thus a novel target for preventing and treating cancer. In the present study, we explored the function of SIRT3 in non-small cell lung cancer (NSCLC) with the aim of elucidating the underlying mechanisms. We first determined the SIRT3 expression levels by real-time PCR, western blotting and immunohistochemistry on tissue microarrays of paired samples of NSCLC tissue and adjacent normal tissue from 70 patients with associated clinicopathological data. Levels of SIRT3 protein and mRNA were significantly increased in NSCLC tissue, compared with normal tissue (P<0.05). Expression of SIRT3 in NSCLC positively correlated with that of malignant biomarker Ki-67 (P<0.05) and oncogene p-Akt (P<0.05). Patients with higher SIRT3 expression had a shorter overall survival duration (P<0.05). NSCLC tissue of squamous cell carcinoma type had higher SIRT3 expression compared with other types (P<0.05). Furthermore, among the clinicopathological variables examined, SIRT3 expression was correlated only with pathological type (P<0.05). In NSCLC cell lines, we found that downregulation of SIRT3 by siRNA decreased the activation of Akt, and that SIRT3 overexpression caused the activation of Akt. In addition, in a NSCLC cell line, SIRT3 was able to co-immunoprecipitate Akt and co-located with Akt, suggesting that SIRT3 regulates the activation of Akt through post-transcriptional modification. Our findings suggest that SIRT3 promotes the malignancy of NSCLC, showing an oncogenic preference towards squamous cell carcinoma, and that could represent a novel target for treatment.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Molina JR, Yang P, Cassivi SD, Schild SE and Adjei AA: Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 83:584–594. 2008. View Article : Google Scholar : PubMed/NCBI
3	Goldstraw P, Ball D, Jett JR, Le Chevalier T, Lim E, Nicholson AG and Shepherd FA: Non-small-cell lung cancer. Lancet. 378:1727–1740. 2011. View Article : Google Scholar : PubMed/NCBI
4	Pao W and Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol. 12:175–180. 2011. View Article : Google Scholar : PubMed/NCBI
5	Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV and Mann M: Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 325:834–840. 2009. View Article : Google Scholar : PubMed/NCBI
6	Kim SC, Sprung R, Chen Y, Xu Y, Ball H, Pei J, Cheng T, Kho Y, Xiao H, Xiao L, et al: Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell. 23:607–618. 2006. View Article : Google Scholar : PubMed/NCBI
7	Guan KL and Xiong Y: Regulation of intermediary metabolism by protein acetylation. Trends Biochem Sci. 36:108–116. 2011. View Article : Google Scholar :
8	Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, Deng CX and Finkel T: A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci USA. 105:14447–14452. 2008. View Article : Google Scholar : PubMed/NCBI
9	Jing E, Emanuelli B, Hirschey MD, Boucher J, Lee KY, Lombard D, Verdin EM and Kahn CR: Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc Natl Acad Sci USA. 108:14608–14613. 2011. View Article : Google Scholar : PubMed/NCBI
10	Sundaresan NR, Samant SA, Pillai VB, Rajamohan SB and Gupta MP: SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol. 28:6384–6401. 2008. View Article : Google Scholar : PubMed/NCBI
11	Kumar S and Lombard DB: Mitochondrial sirtuins and their relationships with metabolic disease and cancer. Antioxid Redox Signal. 22:1060–1077. 2015. View Article : Google Scholar :
12	Haigis MC, Deng CX, Finley LWS, Kim HS and Gius D: SIRT3 is a mitochondrial tumor suppressor: A scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis. Cancer Res. 72:2468–2472. 2012. View Article : Google Scholar : PubMed/NCBI
13	Finley LWS and Haigis MC: Metabolic regulation by SIRT3: Implications for tumorigenesis. Trends Mol Med. 18:516–523. 2012. View Article : Google Scholar : PubMed/NCBI
14	Alhazzazi TY, Kamarajan P, Verdin E and Kapila YL: Sirtuin-3 (SIRT3) and the hallmarks of cancer. Genes Cancer. 4:164–171. 2013. View Article : Google Scholar : PubMed/NCBI
15	Chen Y, Fu LL, Wen X, Wang XY, Liu J, Cheng Y and Huang J: Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer. Cell Death Dis. 5:e10472014. View Article : Google Scholar : PubMed/NCBI
16	Xiong Y, Wang M, Zhao J, Han Y and Jia L: Sirtuin 3: A Janus face in cancer (Review). Int J Oncol. 49:2227–2235. 2016.PubMed/NCBI
17	Budwit-Novotny DA, McCarty KS, Cox EB, Soper JT, Mutch DG, Creasman WT, Flowers JL and McCarty KS Jr: Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res. 46:5419–5425. 1986.PubMed/NCBI
18	Shin SJ, Roh J, Cha HJ, Choi YD, Kim JM, Min SK, Kim JE, Eom DW, Lee H, Kim HJ, et al: TCL1 expression predicts overall survival in patients with mantle cell lymphoma. Eur J Haematol. 95:583–594. 2015. View Article : Google Scholar : PubMed/NCBI
19	DeLong ER, DeLong DM and Clarke-Pearson DL: Comparing the areas under two or more correlated receiver operating characteristic curves: A nonparametric approach. Biometrics. 44:837–845. 1988. View Article : Google Scholar : PubMed/NCBI
20	Cai MY, Zhang B, He WP, Yang GF, Rao HL, Rao ZY, Wu QL, Guan XY, Kung HF, Zeng YX, et al: Decreased expression of Pinx1 protein is correlated with tumor development and is a new independent poor prognostic factor in ovarian carcinoma. Cancer Sci. 101:1543–1549. 2010. View Article : Google Scholar : PubMed/NCBI
21	Zlobec I, Steele R, Terracciano L, Jass JR and Lugli A: Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer. J Clin Pathol. 60:1112–1116. 2007. View Article : Google Scholar
22	Bell EL, Emerling BM, Ricoult SJH and Guarente L: SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production. Oncogene. 30:2986–2996. 2011. View Article : Google Scholar : PubMed/NCBI
23	Wei L, Zhou Y, Qiao C, Ni T, Li Z, You Q, Guo Q and Lu N: Oroxylin A inhibits glycolysis-dependent proliferation of human breast cancer via promoting SIRT3-mediated SOD2 transcription and HIF1α destabilization. Cell Death Dis. 6:e17142015. View Article : Google Scholar
24	Zhao K, Zhou Y, Qiao C, Ni T, Li Z, Wang X, Guo Q, Lu N and Wei L: Oroxylin A promotes PTEN-mediated negative regulation of MDM2 transcription via SIRT3-mediated deacetylation to stabilize p53 and inhibit glycolysis in wt-p53 cancer cells. J Hematol Oncol. 8:412015. View Article : Google Scholar : PubMed/NCBI
25	Xiao K, Jiang J, Wang W, Cao S, Zhu L, Zeng H, Ouyang R, Zhou R and Chen P: Sirt3 is a tumor suppressor in lung adenocarcinoma cells. Oncol Rep. 30:1323–1328. 2013.PubMed/NCBI
26	Zhao Y, Yang H, Wang X, Zhang R, Wang C and Guo Z: Sirtuin-3 (SIRT3) expression is associated with overall survival in esophageal cancer. Ann Diagn Pathol. 17:483–485. 2013. View Article : Google Scholar : PubMed/NCBI
27	Alhazzazi TY, Kamarajan P, Joo N, Huang JY, Verdin E, D'Silva NJ and Kapila YL: Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer. 117:1670–1678. 2011. View Article : Google Scholar : PubMed/NCBI
28	Li H, Feng Z, Wu W, Li J, Zhang J and Xia T: SIRT3 regulates cell proliferation and apoptosis related to energy metabolism in non-small cell lung cancer cells through deacetylation of NMNAT2. Int J Oncol. 43:1420–1430. 2013.PubMed/NCBI
29	Zhang YY and Zhou LM: Sirt3 inhibits hepatocellular carcinoma cell growth through reducing Mdm2-mediated p53 degradation. Biochem Biophys Res Commun. 423:26–31. 2012. View Article : Google Scholar : PubMed/NCBI
30	Quan Y, Wang N, Chen Q, Xu J, Cheng W, Di M, Xia W and Gao WQ: SIRT3 inhibits prostate cancer by destabilizing oncoprotein c-MYC through regulation of the PI3K/Akt pathway. Oncotarget. 6:26494–26507. 2015. View Article : Google Scholar : PubMed/NCBI
31	Pillai VB, Sundaresan NR and Gupta MP: Regulation of Akt signaling by sirtuins: Its implication in cardiac hypertrophy and aging. Circ Res. 114:368–378. 2014. View Article : Google Scholar : PubMed/NCBI
32	Chan CH, Jo U, Kohrman A, Rezaeian AH, Chou PC, Logothetis C and Lin HK: Posttranslational regulation of Akt in human cancer. Cell Biosci. 4:592014. View Article : Google Scholar : PubMed/NCBI
33	Risso G, Blaustein M, Pozzi B, Mammi P and Srebrow A: Akt/PKB: One kinase, many modifications. Biochem J. 468:203–214. 2015. View Article : Google Scholar : PubMed/NCBI
34	Scholzen T and Gerdes J: The Ki-67 protein: From the known and the unknown. J Cell Physiol. 182:311–322. 2000. View Article : Google Scholar : PubMed/NCBI
35	Bauer TM, Patel MR and Infante JR: Targeting PI3 kinase in cancer. Pharmacol Ther. 146:53–60. 2015. View Article : Google Scholar
36	Testa JR and Bellacosa A: AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA. 98:10983–10985. 2001. View Article : Google Scholar : PubMed/NCBI
37	Sundaresan NR, Pillai VB, Wolfgeher D, Samant S, Vasudevan P, Parekh V, Raghuraman H, Cunningham JM, Gupta M and Gupta MP: The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci Signal. 4:ra462011. View Article : Google Scholar : PubMed/NCBI
38	George J, Nihal M, Singh CK, Zhong W, Liu X and Ahmad N: Pro-proliferative function of mitochondrial sirtuin deacetylase SIRT3 in human melanoma. J Invest Dermatol. 136:809–818. 2016. View Article : Google Scholar : PubMed/NCBI
39	Choi J, Koh E, Lee YS, Lee HW, Kang HG, Yoon YE, Han WK, Choi KH and Kim KS: Mitochondrial Sirt3 supports cell proliferation by regulating glutamine-dependent oxidation in renal cell carcinoma. Biochem Biophys Res Commun. 474:547–553. 2016. View Article : Google Scholar : PubMed/NCBI
40	Weinstein IB: Cancer. Addiction to oncogenes - the Achilles heal of cancer. Science. 297:63–64. 2002. View Article : Google Scholar : PubMed/NCBI
41	Fisher GH, Wellen SL, Klimstra D, Lenczowski JM, Tichelaar JW, Lizak MJ, Whitsett JA, Koretsky A and Varmus HE: Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 15:3249–3262. 2001. View Article : Google Scholar : PubMed/NCBI