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. 2013 Aug 27;4(9):702–710. doi: 10.1007/s13238-013-3054-5

Inhibition of SIRT6 in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics

Yewei Liu 1,2, Qian Reuben Xie 1, Boshi Wang 1, Jiaxiang Shao 1, Tingting Zhang 1, Tengyuan Liu 1, Gang Huang 2,✉, Weiliang Xia 1,3,✉
PMCID: PMC4875531  PMID: 23982738

Abstract

SIRT6 is an important histone modifying protein that regulates DNA repair, telomere maintenance, energy metabolism, and target gene expression. Recently SIRT6 has been identified as a tumor suppressor and is down-regulated in certain cancer types, but not in other cancers. From deposited gene profiling studies we found that SIRT6 was overexpressed in prostate tumors, compared with normal or paratumor prostate tissues. Tissue micro-array studies confirmed the higher levels of SIRT6 in both prostate tumor tissues and prostate cancer cells than in their normal counterparts. Knockdown of SIRT6 in human prostate cancer cells led to sub-G1 phase arrest of cell cycle, increased apoptosis, elevated DNA damage level and decrease in BCL2 gene expression. Moreover, SIRT6-de-ficiency reduced cell viability and enhanced chemotherapeutics sensitivity. Taken together, this study provides the first evidence of SIRT6 overexpression in human prostate cancer, and SIRT6 regulation could be exploited for prostate cancer therapy.

Keywords: SI RT6, overexpression, prostate cancer, therapy

Footnotes

These authors contributed equally to the work.

Contributor Information

Gang Huang, Email: huang2802@163.com.

Weiliang Xia, Email: wlxia@sjtu.edu.cn.

References

  1. Bauer I, Grozio A, Lasiglie D, Basile G, Sturla L, Magnone M, Sociali G, Soncini D, Caffa I, Poggi A, et al. The NAD+-dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses. J Biol Chem. 2012;287:40924–40937. doi: 10.1074/jbc.M112.405837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bosch-Presegue L, Vaquero A. The dual role of sirtuins in cancer. Genes Cancer. 2011;2:648–662. doi: 10.1177/1947601911417862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cardus A, Uryga AK, Walters G, Erusalimsky JD. SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence. Cardiovasc Res. 2013;97:571–579. doi: 10.1093/cvr/cvs352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Ann Rev Pathol. 2010;5:253–295. doi: 10.1146/annurev.pathol.4.110807.092250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674. doi: 10.1016/j.cell.2011.02.013. [DOI] [PubMed] [Google Scholar]
  6. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA: a cancer journal for clinicians. 2011;61:69–90. doi: 10.3322/caac.20107. [DOI] [PubMed] [Google Scholar]
  7. Kaidi A, Weinert BT, Choudhary C, Jackson SP. Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science. 2010;329:1348–1353. doi: 10.1126/science.1192049. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  8. Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, McCord RA, Ongaigui KC, Boxer LD, Chang HY, et al. SIRT6 links histone H3 lysine 9 deacetylation to NFkappaB-dependent gene expression and organismal life span. Cell. 2009;136:62–74. doi: 10.1016/j.cell.2008.10.052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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:e1002153. doi: 10.1371/journal.pgen.1002153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Khongkow M, Olmos Y, Gong C, Gomes AR, Monteiro LJ, Yague E, Cavaco TB, Khongkow P, Man EP, Laohasinnarong S, et al. SIRT6 modulates pa epirubicin resistance and survival in breast cancer. Carcinogenesis. 2013;34:1476–1486. doi: 10.1093/carcin/bgt098. [DOI] [PubMed] [Google Scholar]
  11. Liszt G, Ford E, Kurtev M, Guarente L. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem. 2005;280:21313–21320. doi: 10.1074/jbc.M413296200. [DOI] [PubMed] [Google Scholar]
  12. Marquardt JU, Fischer K, Baus K, Kashyap A, Ma S, Krupp M, Linke M, Teufel A, Zechner U, Strand D, et al. Hepatology. 2013. SIRT6 dependent genetic and epigenetic alterations are associated with poor clinical outcome in HCC patients. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. McCord RA, Michishita E, Hong T, Berber E, Boxer LD, Kusumoto R, Guan S, Shi X, Gozani O, Burlingame AL, et al. SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair. Aging. 2009;1:109–121. doi: 10.18632/aging.100011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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;16:4623–4635. doi: 10.1091/mbc.E05-01-0033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Min L, Ji Y, Bakiri L, Qiu Z, Cen J, Chen X, Chen L, Scheuch H, Zheng H, Qin L, et al. Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin. Nat Cell Biol. 2012;14:1203–1211. doi: 10.1038/ncb2590. [DOI] [PubMed] [Google Scholar]
  16. Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006;124:315–329. doi: 10.1016/j.cell.2005.11.044. [DOI] [PubMed] [Google Scholar]
  17. Sebastian C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, Ram O, Truelove J, Guimaraes AR, Toiber D, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell. 2012;151:1185–1199. doi: 10.1016/j.cell.2012.10.047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Shah RB, Mehra R, Chinnaiyan AM, Shen R, Ghosh D, Zhou M, Macvicar GR, Varambally S, Harwood J, Bismar TA, et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. 2004;64:9209–9216. doi: 10.1158/0008-5472.CAN-04-2442. [DOI] [PubMed] [Google Scholar]
  19. Song NY, Surh YJ. Janus-faced role of SIRT1 in tumorigenesis. Ann N Y Acad Sci. 2012;1271:10–19. doi: 10.1111/j.1749-6632.2012.06762.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sundaresan NR, Vasudevan P, Zhong L, Kim G, Samant S, Parekh V, Pillai VB, Ravindra PV, Gupta M, Jeevanandam V, et al. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat Med. 2012;18:1643–1650. doi: 10.1038/nm.2961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22. doi: 10.1016/j.ccr.2010.05.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Van Meter M, Mao Z, Gorbunova V, Seluanov A. SIRT6 overexpression induces massive apoptosis in cancer cells but not in normal cells. Cell Cycle. 2011;10:3153–3158. doi: 10.4161/cc.10.18.17435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Xiao C, Wang RH, Lahusen TJ, Park O, Bertola A, Maruyama T, Reynolds D, Chen Q, Xu X, Young HA, et al. Progression of chronic liver inflammation and fibrosis driven by activation of c-JUN signaling in Sirt6 mutant mice. J Biol Chem. 2012;287:41903–41913. doi: 10.1074/jbc.M112.415182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Xie QR, Liu Y, Shao J, Yang J, Liu T, Zhang T, Wang B, Mruk DD, Silvestrini B, Cheng CY, et al. Male contraceptive Adjudin is a potential anti-cancer drug. Biochem Pharmacol. 2013;85:345–355. doi: 10.1016/j.bcp.2012.11.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Xie X, Zhang H, Gao P, Wang L, Zhang A, Xie S, Li J. Overexpression of SIRT6 in porcine fetal fibroblasts attenuates cytotoxicity and premature senescence caused by D-galactose and tert-butylhydroperoxide. DNA Cell Biol. 2012;31:745–752. doi: 10.1089/dna.2011.1435. [DOI] [PubMed] [Google Scholar]
  26. Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell. 2010;140:280–293. doi: 10.1016/j.cell.2009.12.041. [DOI] [PMC free article] [PubMed] [Google Scholar]

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