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Gankyrin as a potential therapeutic target for cancer

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Abstract

Gankyrin is an oncoprotein that plays a central role in the development of cancer. Although researchers have increasingly focused on the relationships of gankyrin with carcinogenesis, metastasis and prognosis of different cancers, the molecular mechanisms are still unclear. In recent years, several interacting partners of gankyrin and cell signaling pathways regulated by gankyrin have been elucidated. In addition, accumulating evidence has indicated the contribution of microRNAs to regulating gankyrin expression in tumor cells. In this review, we summarize the major known roles of gankyrin in cancer cells and highlight the potential clinical relevance of targeting gankyrin.

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References

  1. Zhang C, Yuan X, Zhang Y (2016) The co-expression of GPER and Gankyrin in ovarian endometriosis and its correlation with the rASRM stages. Arch Gynecol Obstet 293:133–141. doi:10.1007/s00404-015-3807-x

    Article  CAS  PubMed  Google Scholar 

  2. Zhao X, Liu F, Zhang Y et al (2016) Prognostic and clinicopathological significance of Gankyrin overexpression in cancers: evidence from a meta-analysis. Onco Targets Ther 9:1961–1968. doi:10.2147/OTT.S101687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nakamura Y, Umehara T, Tanaka A et al (2007) Purification, crystallization and preliminary X-ray diffraction analysis of the non-ATPase subunit Nas6 in complex with the ATPase subunit Rpt3 of the 26S proteasome from Saccharomyces cerevisiae. Acta Crystallogr Sect F Struct Biol Cryst Commun 63:190–192. doi:10.1107/S1744309107004848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gao L, Xie H, Dong L et al (2014) Gankyrin is essential for hypoxia enhanced metastatic potential in breast cancer cells. Mol Med Rep 9:1032–1036. doi:10.3892/mmr.2013.1860

    Article  CAS  PubMed  Google Scholar 

  5. Kim KH, Lim HJ, Kim YJ et al (2014) The oncoprotein, gankyrin, is up-regulated in middle ear cholesteatoma. Acta Otolaryngol 134:238–243. doi:10.3109/00016489

    Article  CAS  PubMed  Google Scholar 

  6. Nanaware PP, Ramteke MP, Somavarapu AK et al (2014) Discovery of multiple interacting partners of gankyrin, a proteasomal chaperone and an oncoprotein--evidence for a common hot spot site at the interface and its functional relevance. Proteins 82:1283–1300. doi:10.1002/prot.24494

    Article  CAS  PubMed  Google Scholar 

  7. Nakamura Y, Nakano K, Umehara T et al (2007) Structure of the oncoprotein gankyrin in complex with S6 ATPase of the 26S proteasome. Structure 15:179–189. doi:10.1016/j.str.2006.11.015

    Article  CAS  PubMed  Google Scholar 

  8. Nakamura Y, Umehara T, Tanaka A et al (2007) Structural basis for the recognition between the regulatory particles Nas6 and Rpt3 of the yeast 26S proteasome. Biochem Biophys Res Commun 359:503–509. doi:10.1016/j.bbrc.2007.05.138

    Article  CAS  PubMed  Google Scholar 

  9. Dawson S, Higashitsuji H, Wilkinson AJ et al (2006) Gankyrin: a new oncoprotein and regulator of pRb and p53. Trends Cell Biol 16:229–233. doi:10.1016/j.tcb.2006.03.001

    Article  CAS  PubMed  Google Scholar 

  10. Mayer RJ, Fujita J (2006) Gankyrin, the 26 S proteasome, the cell cycle and cancer. Biochem Soc Trans 34:746–748. doi:10.1042/BST0340746

    Article  CAS  PubMed  Google Scholar 

  11. Dawson S, Apcher S, Mee M et al (2002) Gankyrin is an ankyrin-repeat oncoprotein that interacts with CDK4 kinase and the S6 ATPase of the 26 S proteasome. J Biol Chem 277:10893–10902. doi:10.1074/jbc.M107313200

    Article  CAS  PubMed  Google Scholar 

  12. Higashitsuji H, Higashitsuji H, Itoh K et al (2005) The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell 8:75–87. doi:10.1016/j.ccr.2005.06.006

    Article  CAS  PubMed  Google Scholar 

  13. Lozano G, Zambetti GP (2005) Gankyrin: an intriguing name for a novel regulator of p53 and RB. Cancer Cell 8:3–4. doi:10.1016/j.ccr.2005.06.014

    Article  CAS  PubMed  Google Scholar 

  14. Sun W, Ding J, Wu K et al (2011) Gankyrin-mediated dedifferentiation facilitates the tumorigenicity of rat hepatocytes and hepatoma cells. Hepatology 54:1259–1272. doi:10.1002/hep.24530

    Article  CAS  PubMed  Google Scholar 

  15. Luo T, Fu J, Xu A (2015) PSMD10/gankyrin induces autophagy to promote tumor progression through cytoplasmic interaction with ATG7 and nuclear transactivation of ATG7 expression. Autophagy 23:1–17. doi:10.1080/15548627

    Article  Google Scholar 

  16. Yang C, Tan YX, Yang GZ et al (2016) Gankyrin has an antioxidative role through the feedback regulation of Nrf2 in hepatocellular carcinoma. J Exp Med 213:859–875. doi:10.1084/jem.20151208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Iakova P, Timchenko L, Timchenko NA (2011) Intracellular signaling and hepatocellular carcinoma. Semin Cancer Biol 21:28–34. doi:10.1016/j.semcancer

    Article  CAS  PubMed  Google Scholar 

  18. Zheng T, Hong X, Wang J et al (2014) Gankyrin promotes tumor growth and metastasis through activation of IL-6/STAT3 signaling in human cholangiocarcinoma. Hepatology 59:935–946. doi:10.1002/hep.26705

    Article  CAS  PubMed  Google Scholar 

  19. Dong LW, Yang GZ, Pan YF et al (2011) The oncoprotein p28GANK establishes a positive feedback loop in beta-catenin signaling. Cell Res 21:1248–1261. doi:10.1038/cr.2011.103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li J, Tian F, Li D et al (2014) MiR-605 represses PSMD10/Gankyrin and inhibits intrahepatic cholangiocarcinoma cell progression. FEBS Lett 588:3491–3500. doi:10.1016/j.febslet

    Article  CAS  PubMed  Google Scholar 

  21. Liu Y, Xu J, Jiang M et al (2015) Association between functional PSMD10 Rs111638916 variant regulated by MiR-505 and gastric cancer risk in a Chinese population. Cell Physiol Biochem 37:1010–1017. doi:10.1159/000430227

    Article  CAS  PubMed  Google Scholar 

  22. Higashitsuji H, Liu Y, Mayer RJ et al (2005) The oncoprotein gankyrin negatively regulates both p53 and RB by enhancing proteasomal degradation. Cell Cycle 4:1335–1337. doi:10.4161/cc.4.10.2107

    Article  CAS  PubMed  Google Scholar 

  23. Li J, Knobloch TJ, Kresty LA et al (2011) Gankyrin, a biomarker for epithelial carcinogenesis, is overexpressed in human oral cancer. Anticancer Res 31:2683–2692

    CAS  PubMed  Google Scholar 

  24. Jing H, Zhang G, Meng L et al (2014) Gradually elevated expression of Gankyrin during human hepatocarcinogenesis and its clinicopathological significance. Sci Rep 4:5503. doi:10.1038/srep05503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang WP, Yan XL, Li WM et al (2015) Clinicopathologic features and prognostic implications of Gankyrin protein expression in non-small cell lung cancer. Pathol Res Pract 211:939–947. doi:10.1016/j.prp.2015.09.010

    Article  CAS  PubMed  Google Scholar 

  26. Liu Y, Zhang J, Qian W et al (2014) Gankyrin is frequently overexpressed in cervical high grade disease and is associated with cervical carcinogenesis and metastasis. PLoS One 9:e95043. doi:10.1371/journal.pone.0095043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Umemura A, Itoh Y, Itoh K et al (2008) Association of gankyrin protein expression with early clinical stages and insulin-like growth factor-binding protein 5 expression in human hepatocellular carcinoma. Hepatology 47:493–502. doi:10.1002/hep.22027

    Article  CAS  PubMed  Google Scholar 

  28. Qiu W, Wu J, Walsh EM et al (2008) Retinoblastoma protein modulates gankyrin-MDM2 in regulation of p53 stability and chemosensitivity in cancer cells. Oncogene 27:4034–4043. doi:10.1038/onc.2008.43

    Article  CAS  PubMed  Google Scholar 

  29. Fu J, Chen Y, Cao J et al (2011) p28GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1alpha pathways. Hepatology 53:181–192. doi:10.1002/hep.24015

    Article  CAS  PubMed  Google Scholar 

  30. Ferraiuolo M, Di Agostino S, Blandino G et al (2016) Oncogenic intra-p53 family member interactions in human cancers. Front Oncol 6:77. doi:10.3389/fonc.2016.00077

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chuang LS, Ito K, Ito Y (2013) RUNX family: regulation and diversification of roles through interacting proteins. Int J Cancer 132:1260–1271. doi:10.1002/ijc.27964

    Article  CAS  PubMed  Google Scholar 

  32. He W, Wang X, Chen L et al (2012) A crosstalk imbalance between p27(Kip1) and its interacting molecules enhances breast carcinogenesis. Cancer Biother Radiopharm 27:399–402. doi:10.1089/cbr.2010.0802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Krzywda S, Brzozowski AM, Higashitsuji H et al (2004) The crystal structure of gankyrin, an oncoprotein found in complexes with cyclin-dependent kinase 4, a 19 S proteasomal ATPase regulator, and the tumor suppressors Rb and p53. J Biol Chem 279:1541–1545. doi:10.1074/jbc.M310265200

    Article  CAS  PubMed  Google Scholar 

  34. Chapman AM, Rogers BE, McNaughton BR (2014) Characterization of the binding interaction between the oncoprotein gankyrin and a grafted S6 ATPase. Biochemistry 53:6857–6859. doi:10.1021/bi5012354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gasparini C, Celeghini C, Monasta L et al (2014) NF-kappaB pathways in hematological malignancies. Cell Mol Life Sci 71:2083–2102. doi:10.1007/s00018-013-1545-4

    Article  CAS  PubMed  Google Scholar 

  36. Lu X, Yarbrough WG (2015) Negative regulation of RelA phosphorylation: emerging players and their roles in cancer. Cytokine Growth Factor Rev 26:7–13. doi:10.1016/j.cytogfr.2014.09.003

    Article  CAS  PubMed  Google Scholar 

  37. Jakkampudi A, Jangala R, Reddy BR et al (2016) NF-kappaB in acute pancreatitis: mechanisms and therapeutic potential. Pancreatology 16:477–488. doi:10.1016/j.pan.2016.05.001

    Article  CAS  PubMed  Google Scholar 

  38. Chen Y, Li HH, Fu J et al (2007) Oncoprotein p28 GANK binds to RelA and retains NF-kappaB in the cytoplasm through nuclear export. Cell Res 17:1020–1029. doi:10.1038/cr.2007.99

    Article  CAS  PubMed  Google Scholar 

  39. Higashitsuji H, Higashitsuji H, Liu Y et al (2007) The oncoprotein gankyrin interacts with RelA and suppresses NF-kappaB activity. Biochem Biophys Res Commun 363:879–884. doi:10.1016/j.bbrc.2007.09.072

    Article  CAS  PubMed  Google Scholar 

  40. Yamagata K (2014) Roles of HNF1alpha and HNF4alpha in pancreatic beta-cells: lessons from a monogenic form of diabetes (MODY). Vitam Horm 95:407–423. doi:10.1016/B978-0-12-800174-5.00016-8

    Article  CAS  PubMed  Google Scholar 

  41. Walesky C, Apte U (2015) Role of hepatocyte nuclear factor 4alpha (HNF4alpha) in cell proliferation and cancer. Gene Expr 16:101–108. doi:10.3727/105221615X14181438356292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Watson AS, Mortensen M, Simon AK (2011) Autophagy in the pathogenesis of myelodysplastic syndrome and acute myeloid leukemia. Cell Cycle 10:1719–1725. doi:10.4161/cc.10.11.15673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cui J, Gong Z, Shen HM (2013) The role of autophagy in liver cancer: molecular mechanisms and potential therapeutic targets. Biochim Biophys Acta 1836:15–26. doi:10.1016/j.bbcan.2013.02.003

    Article  CAS  PubMed  Google Scholar 

  44. Subramani S, Malhotra V (2013) Non-autophagic roles of autophagy-related proteins. EMBO Rep 14:143–151. doi:10.1038/embor.2012.220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kim J, Keum YS (2016) NRF2, a key regulator of antioxidants with two faces towards cancer. Oxidative Med Cell Longev 2016:2746457. doi:10.1155/2016/2746457

    Article  CAS  Google Scholar 

  46. Lu MC, Ji JA, Jiang ZY et al (2016) The Keap1-Nrf2-ARE pathway as a potential preventive and therapeutic target: an update. Med Res Rev 36:924–963. doi:10.1002/med.21396

    Article  CAS  PubMed  Google Scholar 

  47. Menegon S, Columbano A, Giordano S (2016) The dual roles of NRF2 in cancer. Trends Mol Med 22:578–593. doi:10.1016/j.molmed.2016.05.002

    Article  CAS  PubMed  Google Scholar 

  48. Wang X, Jiang B, Zhang Y (2016) Gankyrin regulates cell signaling network. Tumour Biol 37:5675–5682. doi:10.1007/s13277-016-4854-z

    Article  CAS  PubMed  Google Scholar 

  49. Pei T, Li Y, Wang J et al (2015) YAP is a critical oncogene in human cholangiocarcinoma. Oncotarget 6:17206–17220. doi:10.18632/oncotarget.4043

    Article  PubMed  PubMed Central  Google Scholar 

  50. Zhao X, Fu J, Xu A et al (2015) Gankyrin drives malignant transformation of chronic liver damage-mediated fibrosis via the Rac1/JNK pathway. Cell Death Dis 6:e1751. doi:10.1038/cddis.2015.120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen J, Bai M, Ning C et al (2016) Gankyrin facilitates follicle-stimulating hormone-driven ovarian cancer cell proliferation through the PI3K/AKT/HIF-1alpha/cyclin D1 pathway. Oncogene 35:2506–2517. doi:10.1038/onc.2015.316

    Article  CAS  PubMed  Google Scholar 

  52. Qin X, Wang X, Liu F et al (2016) Gankyrin activates mTORC1 signaling by accelerating TSC2 degradation in colorectal cancer. Cancer Lett 376:83–94. doi:10.1016/j.canlet.2016.03.013

    Article  CAS  PubMed  Google Scholar 

  53. Sun S, Irvine KD (2016) Cellular organization and cytoskeletal regulation of the Hippo signaling network. Trends Cell Biol 26:694–704. doi:10.1016/j.tcb.2016.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kang W, Cheng AS, Yu J et al (2016) Emerging role of Hippo pathway in gastric and other gastrointestinal cancers. World J Gastroenterol 22:1279–1288. doi:10.3748/wjg.v22.i3.1279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Xiao Y, Leach J, Wang J et al (2016) Hippo/yap signaling in cardiac development and regeneration. Curr Treat Options Cardiovasc Med 18:38. doi:10.1007/s11936-016-0461-y

    Article  PubMed  Google Scholar 

  56. Yarza R, Vela S, Solas M et al (2015) C-Jun N-terminal kinase (JNK) signaling as a therapeutic target for Alzheimer's disease. Front Pharmacol 6:321. doi:10.3389/fphar.2015.00321

    Article  CAS  PubMed  Google Scholar 

  57. Yan D, An G, Kuo MT (2016) C-Jun N-terminal kinase signalling pathway in response to cisplatin. J Cell Mol Med 20:2013–2019. doi:10.1111/jcmm.12908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yang SX, Polley E, Lipkowitz S (2016) New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer. Cancer Treat Rev 45:87–96. doi:10.1016/j.ctrv.2016.03.004

    Article  CAS  PubMed  Google Scholar 

  59. Robbins HL, Hague A (2015) The PI3K/Akt pathway in tumors of endocrine tissues. Front Endocrinol (Lausanne) 6:188. doi:10.3389/fendo.2015.00188

    Article  Google Scholar 

  60. Singh SS, Yap WN, Arfuso F et al (2015) Targeting the PI3K/Akt signaling pathway in gastric carcinoma: a reality for personalized medicine? World J Gastroenterol 21:12261–12273. doi:10.3748/wjg.v21.i43.12261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang J, Yang Y, Zhang Z et al (2013) Gankyrin plays an essential role in estrogen-driven and GPR30-mediated endometrial carcinoma cell proliferation via the PTEN/PI3K/AKT signaling pathway. Cancer Lett 339:279–287. doi:10.1016/j.canlet.2012.10.037

    Article  CAS  PubMed  Google Scholar 

  62. Ren W, Yin J, Duan J et al (2016) mTORC1 signaling and IL-17 expression: defining pathways and possible therapeutic targets. Eur J Immunol 46:291–299. doi:10.1002/eji.201545886

    Article  CAS  PubMed  Google Scholar 

  63. Wang X, Chu Y, Wang W et al (2016) mTORC signaling in hematopoiesis. Int J Hematol 103:510–518. doi:10.1007/s12185-016-1944-z

    Article  CAS  PubMed  Google Scholar 

  64. Armijo ME, Campos T, Fuentes-Villalobos F et al (2016) Rheb signaling and tumorigenesis: mTORC1 and new horizons. Int J Cancer 138:1815–1823. doi:10.1002/ijc.29707

    Article  CAS  PubMed  Google Scholar 

  65. Song S, Ajani JA (2013) The role of microRNAs in cancers of the upper gastrointestinal tract. Nat Rev Gastroenterol Hepatol 10:109–118. doi:10.1038/nrgastro.2012.210

    Article  CAS  PubMed  Google Scholar 

  66. Nugent M (2015) microRNA and bone cancer. Adv Exp Med Biol 889:201–230. doi:10.1007/978-3-319-23730-5_11

    Article  CAS  PubMed  Google Scholar 

  67. Rachagani S, Macha MA, Heimann N et al (2015) Clinical implications of miRNAs in the pathogenesis, diagnosis and therapy of pancreatic cancer. Adv Drug Deliv Rev 81:16–33. doi:10.1016/j.addr.2014.10.020

    Article  CAS  PubMed  Google Scholar 

  68. Her GM, Hsu CC, Hong JR et al (2011) Overexpression of gankyrin induces liver steatosis in zebrafish (Danio rerio). Biochim Biophys Acta 1811:536–548. doi:10.1016/j.bbalip.2011.06.011

    Article  CAS  PubMed  Google Scholar 

  69. Misiewicz-Krzeminska I, Sarasquete ME, Quwaider D et al (2013) Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication. Haematologica 98:640–648. doi:10.3324/haematol.2012.070011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Thakur PK, Hassan I (2011) Discovering a potent small molecule inhibitor for gankyrin using de novo drug design approach. Int J Comput Biol Drug Des 4:373–386. doi:10.1504/IJCBDD.2011.044404

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology, the Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China

    Chongchong Wang

  2. Department of Orthopaedics, the Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui Province, 230601, China

    Li Cheng

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Correspondence to Li Cheng.

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This work is supported by the Natural Science Foundation of Anhui Province (1708085QH215) and the Foundation of Anhui Medical University (2015xkj034) to Li Cheng.

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Wang, C., Cheng, L. Gankyrin as a potential therapeutic target for cancer. Invest New Drugs 35, 655–661 (2017). https://doi.org/10.1007/s10637-017-0474-8

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