Science China Life Sciences

, Volume 61, Issue 7, pp 808–814 | Cite as

Epigenetic mechanism of survivin dysregulation in human cancer

  • Hui Lyu
  • Jingcao Huang
  • Zhimin He
  • Bolin Liu


Survivin (coding gene BIRC5) is a dual functional protein acting as a critical inhibitor of apoptosis (IAP) and key regulator of cell cycle progression. It is usually produced in embryonic tissues during development and undetectable in most adult tissues. Overexpression of Survivin frequently occurs in various human cancers and increased Survivin correlates with poor clinic outcome, tumor recurrence, and therapeutic resistance. Because of its selective expression in tumor, but not normal tissues, Survivin has been recognized as an attractive target for cancer treatment. Although several therapeutic approaches targeting Survivin are actively under clinical trials in human cancers, to date no Survivin-targeted therapy has been approved for cancer treatment. Numerous studies have devoted to uncovering the underlying mechanism resulting in Survivin dysregulation at multiple levels, such as transcriptional and post-transcriptional regulation. The current article provides a literature review on the transcriptional and epigenetic regulation of Survivin expression in human cancers. We focus on the impact of DNA methylation and histone modifications, including specific lysine methylation, demethylation, and acetylation on the expression of Survivin. The latest development of epigenetic approaches targeting Survivin for cancer treatment are also discussed.


Survivin epigenetics DNA methylation histone modification cancer therapy 


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This work was supported by the National Institutes of Health/National Cancer Institute (NIH/NCI) (R01CA201011) and the National Natural Science Foundation of China (81472763 to Bolin Liu).


  1. Acquati, S., Greco, A., Licastro, D., Bhagat, H., Ceric, D., Rossini, Z., Grieve, J., Shaked-Rabi, M., Henriquez, N.V., Brandner, S., Stupka, E., and Marino, S. (2013). Epigenetic regulation of survivin by Bmi1 is cell type specific during corticogenesis and in gliomas. Stem Cells 31, 190–202.CrossRefPubMedGoogle Scholar
  2. Altieri, D.C. (1994a). Molecular cloning of effector cell protease receptor- 1, a novel cell surface receptor for the protease factor Xa. J Biol Chem 269, 3139–3142.PubMedGoogle Scholar
  3. Altieri, D.C. (1994b). Splicing of effector cell protease receptor-1 mRNA is modulated by an unusual retained intron. Biochemistry 33, 13848–13–855.CrossRefGoogle Scholar
  4. Altieri, D.C. (2003). Validating survivin as a cancer therapeutic target. Nat Rev Cancer 3, 46–54.CrossRefPubMedGoogle Scholar
  5. Altieri, D.C. (2008). Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8, 61–70.CrossRefPubMedGoogle Scholar
  6. Ambrosini, G., Adida, C., and Altieri, D.C. (1997). A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3, 917–921.CrossRefPubMedGoogle Scholar
  7. Angileri, F.F., Aguennouz, M.H., Conti, A., La Torre, D., Cardali, S., Crupi, R., Tomasello, C., Germanò, A., Vita, G., and Tomasello, F. (2008). Nuclear factor-?B activation and differential expression of survivin and Bcl-2 in human grade 2–4 astrocytomas. Cancer 112, 2258–2266.CrossRefPubMedGoogle Scholar
  8. Baylin, S.B., and Jones, P.A. (2011). A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11, 726–734.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Berrada, N., Amzazi, S., Ameziane El Hassani, R., Benbacer, L., El Mzibri, M., Khyatti, M., Chafiki, J., Abbar, M., Al Bouzidi, A., Ameur, A., and Attaleb, M. (2012). Epigenetic alterations of adenomatous polyposis coli (APC), retinoic acid receptor beta (RARbeta) and survivin genes in tumor tissues and voided urine of bladder cancer patients. Cell Mol Biol (Noisy-le-grand) Suppl. 58, OL1744–1751.Google Scholar
  10. Cartron, P.F., Hervouet, E., Debien, E., Olivier, C., Pouliquen, D., Menanteau, J., Loussouarn, D., A. Martin, S., Campone, M., and Vallette, F. M. (2012). Folate supplementation limits the tumourigenesis in rodent models of gliomagenesis. Eur J Cancer 48, 2431–2441.CrossRefPubMedGoogle Scholar
  11. Chang, H.L., Chen, C.Y., Hsu, Y.F., Kuo, W.S., Ou, G., Chiu, P.T., Huang, Y.H., and Hsu, M.J. (2013). Simvastatin induced HCT116 colorectal cancer cell apoptosis through p38MAPK-p53-survivin signaling cascade. Biochim Biophys Acta 1830, 4053–4064.CrossRefPubMedGoogle Scholar
  12. Chaopatchayakul, P., Jearanaikoon, P., Yuenyao, P., and Limpaiboon, T. (2010). Aberrant DNA methylation of apoptotic signaling genes in patients responsive and nonresponsive to therapy for cervical carcinoma. Am J Obstetr Gynecol 202, 281.e1–281.e9.CrossRefGoogle Scholar
  13. Chen, Y., Wang, X., Li, W., Zhang, H., Zhao, C., Li, Y., Wang, Z., and Chen, C. (2011). Sp1 upregulates survivin expression in adenocarcinoma of lung cell line A549. Anat Rec 294, 774–780.CrossRefGoogle Scholar
  14. Cheng, Q., Ling, X., Haller, A., Nakahara, T., Yamanaka, K., Kita, A., Koutoku, H., Takeuchi, M., Brattain, M.G., and Li, F. (2012). Suppression of survivin promoter activity by YM155 involves disruption of Sp1-DNA interaction in the survivin core promoter. Int J Biochem Mol Biol 3, 179–197.PubMedPubMedCentralGoogle Scholar
  15. Coumar, M.S., Tsai, F.Y., Kanwar, J.R., Sarvagalla, S., and Cheung, C.H. (2013). Treat cancers by targeting survivin: just a dream or future reality? Cancer Treat Rev 39, 802–811.CrossRefPubMedGoogle Scholar
  16. Das, P.M., and Singal, R. (2004). DNA methylation and cancer. J Clin Oncol 22, 4632–4642.CrossRefPubMedGoogle Scholar
  17. Estève, P.O., Chin, H.G., and Pradhan, S. (2005). Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters. Proc Natl Acad Sci USA 102, 1000–1005.CrossRefPubMedGoogle Scholar
  18. Estève, P.O., Chin, H.G., and Pradhan, S. (2007). Molecular mechanisms of transactivation and doxorubicin-mediated repression of survivin gene in cancer cells. J Biol Chem 282, 2615–2625.CrossRefPubMedGoogle Scholar
  19. Feng, W., Cai, D., Zhang, B., Lou, G., and Zou, X. (2015). Combination of HDAC inhibitor TSA and silibinin induces cell cycle arrest and apoptosis by targeting survivin and cyclinB1/Cdk1 in pancreatic cancer cells. Biomed Pharmacother 74, 257–264.CrossRefPubMedGoogle Scholar
  20. Hervouet, E., Debien, E., Campion, L., Charbord, J., Menanteau, J., Vallette, F.M., and Cartron, P.F. (2009). Folate supplementation limits the aggressiveness of glioma via the remethylation of DNA Repeats element and genes governing apoptosis and proliferation. Clin Cancer Res 15, 3519–3529.CrossRefPubMedGoogle Scholar
  21. Hervouet, E., Vallette, F.M., and Cartron, P.F. (2010). Impact of the DNA methyltransferases expression on the methylation status of apoptosisassociated genes in glioblastoma multiforme. Cell Death Dis 1, e8.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hirano, H., Maeda, H., Yamaguchi, T., Yokota, S., Mori, M., and Sakoda, S. (2015). Survivin expression in lung cancer: association with smoking, histological types and pathological stages. Oncol Lett 10, 1456–1462.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Huang, J., Lyu, H., Wang, J., and Liu, B. (2015). MicroRNA regulation and therapeutic targeting of survivin in cancer. Am J Cancer Res 5, 20–31.PubMedGoogle Scholar
  24. Huang, K., Li, L., Meng, Y., You, Y., Fu, X., and Song, L. (2014). Arctigenin promotes apoptosis in ovarian cancer cells via the iNOS/NO/STAT3/Survivin signalling. Basic Clin Pharmacol Toxicol 115, 507–511.CrossRefPubMedGoogle Scholar
  25. Kanwar, J.R., Kamalapuram, S.K., and Kanwar, R.K. (2013). Survivin signaling in clinical oncology: a multifaceted dragon. Med Res Rev 33, 765–789.CrossRefPubMedGoogle Scholar
  26. Kim, J.S., Kim, H.A., Seong, M.K., Seol, H., Su Oh, J., Kim, E.K., Wook Chang, J., Hwang, S.G., and Chul Noh, W. (2016). STAT3-survivin signaling mediates a poor response to radiotherapy in HER2-positive breast cancers. Oncotarget 7, 7055–7065.PubMedPubMedCentralGoogle Scholar
  27. Li, F., and Altieri, D.C. (1999). Transcriptional analysis of human survivin gene expression. Biochem J 344 Pt 2, 305–311.Google Scholar
  28. Li, H.L., and Ma, A.N. (2010). Induction of apoptosis of non-small cell lung cancer by a methylated oligonucleotide targeting survivin gene. Cancer Gene Ther 17, 441–446.CrossRefPubMedGoogle Scholar
  29. Li, J.Y., Shi, J., Sang, J.F., Yao, Y.Z., Wang, X.C., and Su, L. (2015). Role of survivin in the pathogenesis of papillary thyroid carcinoma. Genet Mol Res 14, 15102–15111.CrossRefPubMedGoogle Scholar
  30. Liu, J., Du, W., and Fan, D. (2008). Survivin: the promising target in hepatocellular carcinoma gene therapy. Cancer Biol Ther 7, 555–556.CrossRefPubMedGoogle Scholar
  31. Lu, J., Getz, G., Miska, E.A., Alvarez-Saavedra, E., Lamb, J., Peck, D., Sweet-Cordero, A., Ebert, B.L., Mak, R.H., Ferrando, A.A., Downing, J.R., Jacks, T., Horvitz, H.R., and Golub, T.R. (2005). microRNA expression profiles classify human cancers. Nature 435, 834–838.CrossRefPubMedGoogle Scholar
  32. Ma, A.N., Huang, W.L., Wu, Z.N., Hu, J.F., Li, T., Zhou, X.J., and Wang, Y.X. (2010). Induced epigenetic modifications of the promoter chromatin silence survivin and inhibit tumor growth. Biochem Biophys Res Commun 393, 592–597.CrossRefPubMedGoogle Scholar
  33. Ma, A., Lu, J., Zhou, X., and Wang, Y. (2011). Histone deacetylation directs DNA methylation in survivin gene silencing. Biochem Biophys Res Commun 404, 268–272.CrossRefPubMedGoogle Scholar
  34. Ma, J., Zhao, M., Yu, X.D., and Wang, Z.H. (2009). MS-275, a histone deacetylase inhibitor, induces apoptosis and alters survivin gene expression in human myeloma cell line U266 (in Chinese). Ai Zheng 28, 466–471.PubMedGoogle Scholar
  35. Min, L., Ji, Y., Bakiri, L., Qiu, Z., Cen, J., Chen, X., Chen, L., Scheuch, H., Zheng, H., Qin, L., Zatloukal, K., Hui, L., and Wagner, E.F. (2012). Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin. Nat Cell Biol 14, 1203–1211.CrossRefPubMedGoogle Scholar
  36. Mityaev, M.V., Kopantzev, E.P., Buzdin, A.A., Vinogradova, T.V., and Sverdlov, E.D. (2008). Functional significance of a putative Sp1 transcription factor binding site in the survivin gene promoter. Biochem Moscow 73, 1183–1191.CrossRefGoogle Scholar
  37. Nabilsi, N.H., Broaddus, R.R., and Loose, D.S. (2009). DNA methylation inhibits p53-mediated survivin repression. Oncogene 28, 2046–2050.CrossRefPubMedGoogle Scholar
  38. Nakano, J., Huang, C.L., Liu, D., Ueno, M., Sumitomo, S., and Yokomise, H. (2005). Survivin gene expression is negatively regulated by the p53 tumor suppressor gene in non-small cell lung cancer. Int J Oncol 27, 1215–1221.PubMedGoogle Scholar
  39. Papanikolaou, V., Iliopoulos, D., Dimou, I., Dubos, S., Kappas, C., Kitsiou- Tzeli, S., and Tsezou, A. (2011). Survivin regulation by HER2 through NF-?B and c-myc in irradiated breast cancer cells. J Cell Mol Med 15, 1542–1550.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Pennati, M., Folini, M., and Zaffaroni, N. (2008). Targeting survivin in cancer therapy. Expert Opin Ther Targets 12, 463–476.CrossRefPubMedGoogle Scholar
  41. Raj, D., Liu, T., Samadashwily, G., Li, F., and Grossman, D. (2008). Survivin repression by p53, Rb and E2F2 in normal human melanocytes. Carcinogenesis 29, 194–201.CrossRefPubMedGoogle Scholar
  42. Ryan, B.M., O’Donovan, N., and Duffy, M.J. (2009). Survivin: a new target for anti-cancer therapy. Cancer Treatment Rev 35, 553–562.CrossRefGoogle Scholar
  43. Sah, N.K., Khan, Z., Khan, G.J., and Bisen, P.S. (2006). Structural, functional and therapeutic biology of survivin. Cancer Lett 244, 164–171.CrossRefPubMedGoogle Scholar
  44. Sato, A., Asano, T., Ito, K., Sumitomo, M., Asano, T., and Hayakawa, M. (2009). A potential novel combination therapy targeting survivin in renal cancer cells: inhibition of survivin expression by topotecan and hexamethylene bisacetamide. Mol Med Rep 2, 423–428.PubMedGoogle Scholar
  45. Smallwood, A., Estève, P.O., Pradhan, S., and Carey, M. (2007). Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev 21, 1169–1178.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Sokolowska, J., Urbanska, K., Gizinski, S., Wysocka, A., Cywinska, A., and Lechowski, R. (2015). Survivin expression in canine lymphomas in relation with proliferative markers. Pol J Vet Sci 18, 113–122.PubMedCrossRefGoogle Scholar
  47. Tanaka, C., Uzawa, K., Shibahara, T., Yokoe, H., Noma, H., and Tanzawa, H. (2003). Expression of an inhibitor of apoptosis, survivin, in oral carcinogenesis. J Dent Res 82, 607–611.CrossRefPubMedGoogle Scholar
  48. Tsai, Y.J., Tsai, T., Peng, P.C., Li, P.T., and Chen, C.T. (2015). Histone acetyltransferase p300 is induced by p38MAPK after photodynamic therapy: the therapeutic response is increased by the p300HAT inhibitor anacardic acid. Free Radical Biol Med 86, 118–132.CrossRefGoogle Scholar
  49. Vaziri, S.A.J., Hill, J., Chikamori, K., Grabowski, D.R., Takigawa, N., Chawla-Sarkar, M., Rybicki, L.R., Gudkov, A.V., Mekhail, T., Bukowski, R.M., Ganapathi, M.K., and Ganapathi, R. (2005). Sensitization of DNA damage-induced apoptosis by the proteasome inhibitor PS-341 is p53 dependent and involves target proteins 14-3-3 and survivin. Mol Cancer Ther 4, 1880–1890.CrossRefPubMedGoogle Scholar
  50. Wagner, M., Schmelz, K., Dörken, B., and Tamm, I. (2008a). Epigenetic and genetic analysis of the survivin promoter in acute myeloid leukemia. Leukemia Res 32, 1054–1060.CrossRefGoogle Scholar
  51. Wagner, M., Schmelz, K., Dörken, B., and Tamm, I. (2008b). Transcriptional regulation of human survivin by early growth response (Egr)-1 transcription factor. Int J Cancer 122, 1278–1287.CrossRefPubMedGoogle Scholar
  52. Wahdan-Alaswad, R., and Liu, B. (2013). “Sister” miRNAs in cancers. Cell Cycle 12, 3703–3704.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Wang, K., Brems, J.J., Gamelli, R.L., and Holterman, A.X. (2010). Survivin signaling is regulated through nuclear factor-kappa B pathway during glycochenodeoxycholate-induced hepatocyte apoptosis. Biochim Biophys Acta 1803, 1368–1375.CrossRefPubMedGoogle Scholar
  54. Wang, S., Huang, J., Lyu, H., Lee, C.K., Tan, J., Wang, J., and Liu, B. (2013). Functional cooperation of miR-125a, miR-125b, and miR-205 in entinostat-induced downregulation of erbB2/erbB3 and apoptosis in breast cancer cells. Cell Death Dis 4, e556.CrossRefPubMedPubMedCentralGoogle Scholar
  55. Wang, S., Zhu, L., Zuo, W., Zeng, Z., Huang, L., Lin, F., Lin, R., Wang, J., Lu, J., Wang, Q., Lin, L., Dong, H., Wu, W., Zheng, K., Cai, J., Yang, S., Ma, Y., Ye, S., Liu, W., Yu, Y., Tan, J., and Liu, B. (2016). MicroRNA- mediated epigenetic targeting of Survivin significantly enhances the antitumor activity of paclitaxel against non-small cell lung cancer. Oncotarget 7, 37693–37713.PubMedPubMedCentralGoogle Scholar
  56. Weiss, A., Heinz, C., and Groner, B. (2008). Survivin—An inhibitor of apoptosis as a target for peptide based therapy for human breast cancer. J Pept Sci 14, 125–125.Google Scholar
  57. Xu, R., Zhang, P., Huang, J., Ge, S.F., Lu, J., and Qian, G.X. (2007). Sp1 and Sp3 regulate basal transcription of the survivin gene. Biochem Biophys Res Commun 356, 286–292.CrossRefPubMedGoogle Scholar
  58. Yamada, T., Horinaka, M., Shinnoh, M., Yoshioka, T., Miki, T., and Sakai, T. (2013). A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma. Int J Oncol 43, 1080–1086.CrossRefPubMedGoogle Scholar
  59. Yang, J., Song, K., Krebs, T.L., Jackson, M.W., and Danielpour, D. (2008). Rb/E2F4 and Smad2/3 link survivin to TGF-ß-induced apoptosis and tumor progression. Oncogene 27, 5326–5338.CrossRefPubMedPubMedCentralGoogle Scholar
  60. Yang, X., Xiong, G., Chen, X., Xu, X., Wang, K., Fu, Y., Yang, K., and Bai, Y. (2009). Survivin expression in esophageal cancer: correlation with p53 mutations and promoter polymorphism. Dis Esophagus 22, 223–230.CrossRefPubMedGoogle Scholar
  61. Yu, J., Zhang, H., Gu, J., Lin, S., Li, J., Lu, W., Wang, Y., and Zhu, J. (2004). Methylation profiles of thirty four promoter-CpG islands and concordant methylation behaviours of sixteen genes that may contribute to carcinogenesis of astrocytoma. BMC Cancer 4, 65.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Zaffaroni, N., and Daidone, M.G. (2002). Survivin expression and resistance to anticancer treatments: perspectives for new therapeutic interventions. Drug Resist Updates 5, 65–72.CrossRefGoogle Scholar
  63. Zhang, Y., Chen, H., Zhou, S., Wang, S., Zheng, K., Xu, D., Liu, Y., Wang, X., Wang, X., Yan, H.Z., Zhang, L., Liu, Q., Chen, W., and Wang, Y. (2015). Sp1 and c-Myc modulate drug resistance of leukemia stem cells by regulating survivin expression through the ERK-MSK MAPK signaling pathway. Mol Cancer 14, 56.CrossRefPubMedPubMedCentralGoogle Scholar
  64. Zhou, M., Gu, L., Li, F., Zhu, Y., Woods, W.G., and Findley, H.W. (2002). DNA damage induces a novel p53-survivin signaling pathway regulating cell cycle and apoptosis in acute lymphoblastic leukemia cells. J Pharmacol Exp Ther 303, 124–131.CrossRefPubMedGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pathology, School of MedicineUniversity of Colorado Anschutz Medical CampusAuroraUSA
  2. 2.Cancer Research Institute and Affiliated Cancer HospitalGuangzhou Medical UniversityGuangzhouChina
  3. 3.Department of Hematology, Hematologic Research Laboratory, West China HospitalSichuan UniversityChengduChina

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