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Published in: Cancer Cell International 1/2022

Open Access 01-12-2022 | osteosarcoma | Review

Clinicopathological and prognostic value of SIRT6 in patients with solid tumors: a meta-analysis and TCGA data review

Authors: Xiaojing Wu, Shuyuan Wang, Xuanzhu Zhao, Sizhen Lai, Zhen Yuan, Yixiang Zhan, Kemin Ni, Zhaoce Liu, Lina Liu, Ran Xin, Xingyu Zhou, Xin Yin, Xinyu Liu, Xipeng Zhang, Wei Cui, Chunze Zhang

Published in: Cancer Cell International | Issue 1/2022

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Abstract

Purposes

In addition to its role in cellular progression and cancer, SIRT6, a member of nicotinamide adenine dinucleotide (NAD+)-dependent class III deacylase sirtuin family, serves a variety of roles in the body's immune system. In this study, we sought to determine the relationship between the expression of SIRT6 and the clinicopathological outcomes of patients with solid tumours by conducting a meta-analysis of the available data.

Methods

The databases PubMed and ISI Web of Science were searched for relevant literature, and the results were presented here. Using Stata16.0, a meta-analysis was conducted to determine the impact of SIRT6 on clinicopathological characteristics and prognosis in malignancy patients. The results were published in the journal Cancer Research. The dataset from the Cancer Genome Atlas (TCGA) was used to investigate the prognostic significance of SIRT6 in various types of tumors.

Results

The inclusion and exclusion criteria were met by 15 studies. In patients with solid tumours, reduced SIRT6 expression was found to be related with improved overall survival (OS) (HR = 0.66, 95% CI = 0.45–0.97, P < 0.001) as well as improved disease-free survival (DFS) (HR = 0.48, 95% CI = 0.26–0.91, P < 0.001). Low SIRT6 expression was found to be associated with a better OS in breast cancer (HR = 0.49, 95% CI = 0.27–0.89, P = 0.179), but was found to be associated with a worse OS in gastrointestinal cancer (gastric cancer and colon cancer) (HR = 1.83, 95% CI = 1.20–2.79, P = 0.939) after subgroup analysis. In terms of clinicopathological characteristics, SIRT6 expression was found to be linked with distant metastasis (OR = 2.98, 95% CI = 1.59–5.57, P = 0.694). When the data from the TCGA dataset was compared to normal tissue, it was discovered that SIRT6 expression was significantly different in 11 different types of cancers. Meanwhile, reduced SIRT6 expression was shown to be associated with improved OS (P < 0.05), which was consistent with the findings of the meta-analysis. Aside from that, the expression of SIRT6 was found to be associated with both gender and clinical stage.

Conclusion

The overall data of the present meta-analysis indicated that low expression of SIRT6 may predict a favorable survival for patients with solid tumors.
Appendix
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Literature
1.
go back to reference Sosnowska B, Mazidi M, Penson P, Gluba-Brzozka A, Rysz J, Banach M. The sirtuin family members SIRT1, SIRT3 and SIRT6: their role in vascular biology and atherogenesis. Atherosclerosis. 2017;265:275–82.CrossRef Sosnowska B, Mazidi M, Penson P, Gluba-Brzozka A, Rysz J, Banach M. The sirtuin family members SIRT1, SIRT3 and SIRT6: their role in vascular biology and atherogenesis. Atherosclerosis. 2017;265:275–82.CrossRef
2.
go back to reference Lerrer B, Gertler AA, Cohen HY. The complex role of SIRT6 in carcinogenesis. Carcinogenesis. 2016;37(2):108–18.CrossRef Lerrer B, Gertler AA, Cohen HY. The complex role of SIRT6 in carcinogenesis. Carcinogenesis. 2016;37(2):108–18.CrossRef
3.
go back to reference Dong Z, Lei Q, Liu L, Cui H. Function of SIRT6 in tumor initiation and progression. Sheng Wu Gong Cheng Xue Bao. 2016;32(7):870–9.PubMed Dong Z, Lei Q, Liu L, Cui H. Function of SIRT6 in tumor initiation and progression. Sheng Wu Gong Cheng Xue Bao. 2016;32(7):870–9.PubMed
4.
go back to reference Chen T, Sun Z, Liu F, Wang Q. RASSF1A and SIRT6 in non-small cell lung cancer: relationship with clinical outcome. Oncol Lett. 2017;14(5):5759–64.PubMedPubMedCentral Chen T, Sun Z, Liu F, Wang Q. RASSF1A and SIRT6 in non-small cell lung cancer: relationship with clinical outcome. Oncol Lett. 2017;14(5):5759–64.PubMedPubMedCentral
5.
go back to reference Lin H, Hao Y, Zhao Z, Tong Y. Sirtuin 6 contributes to migration and invasion of osteosarcoma cells via the ERK1/2/MMP9 pathway. FEBS Open Bio. 2017;7(9):1291–301.CrossRef Lin H, Hao Y, Zhao Z, Tong Y. Sirtuin 6 contributes to migration and invasion of osteosarcoma cells via the ERK1/2/MMP9 pathway. FEBS Open Bio. 2017;7(9):1291–301.CrossRef
6.
go back to reference Qu N, Hu JQ, Liu L, Zhang TT, Sun GH, Shi RL, et al. SIRT6 is upregulated and associated with cancer aggressiveness in papillary thyroid cancer via BRAF/ERK/Mcl1 pathway. Int J Oncol. 2017;50(5):1683–92.CrossRef Qu N, Hu JQ, Liu L, Zhang TT, Sun GH, Shi RL, et al. SIRT6 is upregulated and associated with cancer aggressiveness in papillary thyroid cancer via BRAF/ERK/Mcl1 pathway. Int J Oncol. 2017;50(5):1683–92.CrossRef
7.
go back to reference Liu Y, Xie QR, Wang B, Shao J, Zhang T, Liu T, et al. Inhibition of SIRT6 in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics. Protein Cell. 2013;4(9):702–10.CrossRef Liu Y, Xie QR, Wang B, Shao J, Zhang T, Liu T, et al. Inhibition of SIRT6 in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics. Protein Cell. 2013;4(9):702–10.CrossRef
8.
go back to reference Jeh SU, Park JJ, Lee JS, Kim DC, Do J, Lee SW, et al. Differential expression of the sirtuin family in renal cell carcinoma: aspects of carcinogenesis and prognostic significance. Urol Oncol. 2017;35(12):675.CrossRef Jeh SU, Park JJ, Lee JS, Kim DC, Do J, Lee SW, et al. Differential expression of the sirtuin family in renal cell carcinoma: aspects of carcinogenesis and prognostic significance. Urol Oncol. 2017;35(12):675.CrossRef
9.
go back to reference Kugel S, Sebastian C, Fitamant J, Ross KN, Saha SK, Jain E, et al. SIRT6 suppresses pancreatic cancer through control of Lin28b. Cell. 2016;165(6):1401–15.CrossRef Kugel S, Sebastian C, Fitamant J, Ross KN, Saha SK, Jain E, et al. SIRT6 suppresses pancreatic cancer through control of Lin28b. Cell. 2016;165(6):1401–15.CrossRef
10.
go back to reference Tian J, Yuan L. Sirtuin 6 inhibits colon cancer progression by modulating PTEN/AKT signaling. Biomed Pharmacother. 2018;106:109–16.CrossRef Tian J, Yuan L. Sirtuin 6 inhibits colon cancer progression by modulating PTEN/AKT signaling. Biomed Pharmacother. 2018;106:109–16.CrossRef
11.
go back to reference Bai L, Lin G, Sun L, Liu Y, Huang X, Cao C, et al. Upregulation of SIRT6 predicts poor prognosis and promotes metastasis of non-small cell lung cancer via the ERK1/2/MMP9 pathway. Oncotarget. 2016;7(26):40377–86.CrossRef Bai L, Lin G, Sun L, Liu Y, Huang X, Cao C, et al. Upregulation of SIRT6 predicts poor prognosis and promotes metastasis of non-small cell lung cancer via the ERK1/2/MMP9 pathway. Oncotarget. 2016;7(26):40377–86.CrossRef
12.
go back to reference Shen X, Li P, Xu Y, Chen X, Sun H, Zhao Y, et al. Association of sirtuins with clinicopathological parameters and overall survival in gastric cancer. Oncotarget. 2017;8(43):74359–70.CrossRef Shen X, Li P, Xu Y, Chen X, Sun H, Zhao Y, et al. Association of sirtuins with clinicopathological parameters and overall survival in gastric cancer. Oncotarget. 2017;8(43):74359–70.CrossRef
13.
go back to reference Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.CrossRef Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.CrossRef
14.
go back to reference Zhang Z, Ha SH, Moon YJ, Hussein UK, Song Y, Kim KM, et al. Inhibition of SIRT6 potentiates the anti-tumor effect of doxorubicin through suppression of the DNA damage repair pathway in osteosarcoma. J Exp Clin Cancer Res. 2020;39(1):247.CrossRef Zhang Z, Ha SH, Moon YJ, Hussein UK, Song Y, Kim KM, et al. Inhibition of SIRT6 potentiates the anti-tumor effect of doxorubicin through suppression of the DNA damage repair pathway in osteosarcoma. J Exp Clin Cancer Res. 2020;39(1):247.CrossRef
15.
go back to reference Han LL, Jia L, Wu F, Huang C. Sirtuin6 (SIRT6) promotes the EMT of hepatocellular carcinoma by stimulating autophagic degradation of E-cadherin. Mol Cancer Res. 2019;17(11):2267–80.CrossRef Han LL, Jia L, Wu F, Huang C. Sirtuin6 (SIRT6) promotes the EMT of hepatocellular carcinoma by stimulating autophagic degradation of E-cadherin. Mol Cancer Res. 2019;17(11):2267–80.CrossRef
16.
go back to reference Bae JS, Noh SJ, Kim KM, Park SH, Hussein UK, Park HS, et al. SIRT6 is involved in the progression of ovarian carcinomas via beta-catenin-mediated epithelial to mesenchymal transition. Front Oncol. 2018;8:538.CrossRef Bae JS, Noh SJ, Kim KM, Park SH, Hussein UK, Park HS, et al. SIRT6 is involved in the progression of ovarian carcinomas via beta-catenin-mediated epithelial to mesenchymal transition. Front Oncol. 2018;8:538.CrossRef
17.
go back to reference Li N, Mao D, Cao YS, Li H, Ren F, Li KY. Downregulation of SIRT6 by miR-34c-5p is associated with poor prognosis and promotes colon cancer proliferation through inhibiting apoptosis via the JAK2/STAT3 signaling pathway. Int J Oncol. 2018;52(5):1515–27.PubMedPubMedCentral Li N, Mao D, Cao YS, Li H, Ren F, Li KY. Downregulation of SIRT6 by miR-34c-5p is associated with poor prognosis and promotes colon cancer proliferation through inhibiting apoptosis via the JAK2/STAT3 signaling pathway. Int J Oncol. 2018;52(5):1515–27.PubMedPubMedCentral
18.
go back to reference Zhu BJ, Yan YJ, Shao BY, Tian LW, Zhou WH. Downregulation of SIRT6 is associated with poor prognosis in patients with non-small cell lung cancer. J Int Med Res. 2018;46(4):1517–27.CrossRef Zhu BJ, Yan YJ, Shao BY, Tian LW, Zhou WH. Downregulation of SIRT6 is associated with poor prognosis in patients with non-small cell lung cancer. J Int Med Res. 2018;46(4):1517–27.CrossRef
19.
go back to reference Zhou JM, Wu A, Yu XT, Zhu JW, Dai H. SIRT6 inhibits growth of gastric cancer by inhibiting JAK2/STAT3 pathway. Oncol Rep. 2017;38(2):1059–66.CrossRef Zhou JM, Wu A, Yu XT, Zhu JW, Dai H. SIRT6 inhibits growth of gastric cancer by inhibiting JAK2/STAT3 pathway. Oncol Rep. 2017;38(2):1059–66.CrossRef
20.
go back to reference Bae JS, Park SH, Jamiyandorj U, Kim KM, Noh SJ, Kim JR, et al. CK2alpha/CSNK2A1 phosphorylates SIRT6 and is involved in the progression of breast carcinoma and predicts shorter survival of diagnosed patients. Am J Pathol. 2016;186(12):3297–315.CrossRef Bae JS, Park SH, Jamiyandorj U, Kim KM, Noh SJ, Kim JR, et al. CK2alpha/CSNK2A1 phosphorylates SIRT6 and is involved in the progression of breast carcinoma and predicts shorter survival of diagnosed patients. Am J Pathol. 2016;186(12):3297–315.CrossRef
21.
go back to reference Ran LK, Chen Y, Zhang ZZ, Tao NN, Ren JH, Zhou L, et al. SIRT6 overexpression potentiates apoptosis evasion in hepatocellular carcinoma via BCL2-associated X protein-dependent apoptotic pathway. Clin Cancer Res. 2016;22(13):3372–82.CrossRef Ran LK, Chen Y, Zhang ZZ, Tao NN, Ren JH, Zhou L, et al. SIRT6 overexpression potentiates apoptosis evasion in hepatocellular carcinoma via BCL2-associated X protein-dependent apoptotic pathway. Clin Cancer Res. 2016;22(13):3372–82.CrossRef
22.
go back to reference Azuma Y, Yokobori T, Mogi A, Altan B, Yajima T, Kosaka T, et al. SIRT6 expression is associated with poor prognosis and chemosensitivity in patients with non-small cell lung cancer. J Surg Oncol. 2015;112(2):231–7.CrossRef Azuma Y, Yokobori T, Mogi A, Altan B, Yajima T, Kosaka T, et al. SIRT6 expression is associated with poor prognosis and chemosensitivity in patients with non-small cell lung cancer. J Surg Oncol. 2015;112(2):231–7.CrossRef
23.
go back to reference Thirumurthi U, Shen J, Xia W, LaBaff AM, Wei Y, Li CW, et al. MDM2-mediated degradation of SIRT6 phosphorylated by AKT1 promotes tumorigenesis and trastuzumab resistance in breast cancer. Sci Signaling. 2014;7(336):ra71.CrossRef Thirumurthi U, Shen J, Xia W, LaBaff AM, Wei Y, Li CW, et al. MDM2-mediated degradation of SIRT6 phosphorylated by AKT1 promotes tumorigenesis and trastuzumab resistance in breast cancer. Sci Signaling. 2014;7(336):ra71.CrossRef
24.
go back to reference Khongkow M, Olmos Y, Gong C, Gomes AR, Monteiro LJ, Yague E, et al. SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer. Carcinogenesis. 2013;34(7):1476–86.CrossRef Khongkow M, Olmos Y, Gong C, Gomes AR, Monteiro LJ, Yague E, et al. SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer. Carcinogenesis. 2013;34(7):1476–86.CrossRef
25.
go back to reference Fiorentino F, Carafa V, Favale G, Altucci L, Mai A, Rotili D. The two-faced role of SIRT6 in cancer. Cancers (Basel). 2021;13(5):1156.CrossRef Fiorentino F, Carafa V, Favale G, Altucci L, Mai A, Rotili D. The two-faced role of SIRT6 in cancer. Cancers (Basel). 2021;13(5):1156.CrossRef
26.
go back to reference Choe M, Brusgard JL, Chumsri S, Bhandary L, Zhao XF, Lu S, et al. The RUNX2 transcription factor negatively regulates SIRT6 expression to alter glucose metabolism in breast cancer cells. J Cell Biochem. 2015;116(10):2210–26.CrossRef Choe M, Brusgard JL, Chumsri S, Bhandary L, Zhao XF, Lu S, et al. The RUNX2 transcription factor negatively regulates SIRT6 expression to alter glucose metabolism in breast cancer cells. J Cell Biochem. 2015;116(10):2210–26.CrossRef
27.
go back to reference Khongkow M, Olmos Y, Gong C, Gomes AR, Monteiro LJ, Yagüe E, et al. SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer. Carcinogenesis. 2013;34(7):1476–86.CrossRef Khongkow M, Olmos Y, Gong C, Gomes AR, Monteiro LJ, Yagüe E, et al. SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer. Carcinogenesis. 2013;34(7):1476–86.CrossRef
28.
go back to reference Liu G, Chen H, Liu H, Zhang W, Zhou J. Emerging roles of SIRT6 in human diseases and its modulators. Med Res Rev. 2021;41(2):1089–137.CrossRef Liu G, Chen H, Liu H, Zhang W, Zhou J. Emerging roles of SIRT6 in human diseases and its modulators. Med Res Rev. 2021;41(2):1089–137.CrossRef
29.
go back to reference Sebastián C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell. 2012;151(6):1185–99.CrossRef Sebastián C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell. 2012;151(6):1185–99.CrossRef
30.
go back to reference Zhang ZG, Qin CY. Sirt6 suppresses hepatocellular carcinoma cell growth via inhibiting the extracellular signal-regulated kinase signaling pathway. Mol Med Rep. 2014;9(3):882–8.CrossRef Zhang ZG, Qin CY. Sirt6 suppresses hepatocellular carcinoma cell growth via inhibiting the extracellular signal-regulated kinase signaling pathway. Mol Med Rep. 2014;9(3):882–8.CrossRef
31.
go back to reference Wang Y, Pan T, Wang H, Li L, Li J, Zhang D, et al. Overexpression of SIRT6 attenuates the tumorigenicity of hepatocellular carcinoma cells. Oncotarget. 2017;8(44):76223–30.CrossRef Wang Y, Pan T, Wang H, Li L, Li J, Zhang D, et al. Overexpression of SIRT6 attenuates the tumorigenicity of hepatocellular carcinoma cells. Oncotarget. 2017;8(44):76223–30.CrossRef
32.
go back to reference Mahmud Z, Gomes AR, Lee HJ, Aimjongjun S, Jiramongkol Y, Yao S, et al. EP300 and SIRT1/6 Co-regulate lapatinib sensitivity via modulating FOXO3-acetylation and activity in breast cancer. Cancers (Basel). 2019;11(8):1067.CrossRef Mahmud Z, Gomes AR, Lee HJ, Aimjongjun S, Jiramongkol Y, Yao S, et al. EP300 and SIRT1/6 Co-regulate lapatinib sensitivity via modulating FOXO3-acetylation and activity in breast cancer. Cancers (Basel). 2019;11(8):1067.CrossRef
33.
go back to reference Garcia-Peterson LM, Guzmán-Pérez G, Krier CR, Ahmad N. The sirtuin 6: an overture in skin cancer. Exp Dermatol. 2020;29(2):124–35.CrossRef Garcia-Peterson LM, Guzmán-Pérez G, Krier CR, Ahmad N. The sirtuin 6: an overture in skin cancer. Exp Dermatol. 2020;29(2):124–35.CrossRef
34.
go back to reference Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell. 2005;16(10):4623–35.CrossRef Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell. 2005;16(10):4623–35.CrossRef
35.
go back to reference Tennen RI, Berber E, Chua KF. Functional dissection of SIRT6: identification of domains that regulate histone deacetylase activity and chromatin localization. Mech Ageing Dev. 2010;131(3):185–92.CrossRef Tennen RI, Berber E, Chua KF. Functional dissection of SIRT6: identification of domains that regulate histone deacetylase activity and chromatin localization. Mech Ageing Dev. 2010;131(3):185–92.CrossRef
36.
go back to reference Kawahara TL, Rapicavoli NA, Wu AR, Qu K, Quake SR, Chang HY. Dynamic chromatin localization of Sirt6 shapes stress- and aging-related transcriptional networks. PLoS Genet. 2011;7(6):e1002153.CrossRef Kawahara TL, Rapicavoli NA, Wu AR, Qu K, Quake SR, Chang HY. Dynamic chromatin localization of Sirt6 shapes stress- and aging-related transcriptional networks. PLoS Genet. 2011;7(6):e1002153.CrossRef
Metadata
Title
Clinicopathological and prognostic value of SIRT6 in patients with solid tumors: a meta-analysis and TCGA data review
Authors
Xiaojing Wu
Shuyuan Wang
Xuanzhu Zhao
Sizhen Lai
Zhen Yuan
Yixiang Zhan
Kemin Ni
Zhaoce Liu
Lina Liu
Ran Xin
Xingyu Zhou
Xin Yin
Xinyu Liu
Xipeng Zhang
Wei Cui
Chunze Zhang
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2022
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-022-02511-3

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