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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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TRRAP stimulates the tumorigenic potential of ovarian cancer stem cells

  • Kang, Kyung Taek (Department of Physiology, School of Medicine, Pusan National University) ;
  • Kwon, Yang Woo (Department of Physiology, School of Medicine, Pusan National University) ;
  • Kim, Dae Kyoung (Department of Physiology, School of Medicine, Pusan National University) ;
  • Lee, Su In (Department of Physiology, School of Medicine, Pusan National University) ;
  • Kim, Ki-Hyung (Department of Obstetrics and Gynecology, School of Medicine, Pusan National University) ;
  • Suh, Dong-Soo (Department of Obstetrics and Gynecology, School of Medicine, Pusan National University) ;
  • Kim, Jae Ho (Department of Physiology, School of Medicine, Pusan National University)
  • Received : 2018.02.22
  • Accepted : 2018.05.15
  • Published : 2018.10.31
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Abstract

Ovarian cancer is the most fatal gynecological malignancy in women and identification of new therapeutic targets is essential for the continued development of therapy for ovarian cancer. TRRAP (transformation/transcription domain-associated protein) is an adaptor protein and a component of histone acetyltransferase complex. The present study was undertaken to investigate the roles played by TRRAP in the proliferation and tumorigenicity of ovarian cancer stem cells. TRRAP expression was found to be up-regulated in the sphere cultures of A2780 ovarian cancer cells. Knockdown of TRRAP significantly decreased cell proliferation and the number of A2780 spheroids. In addition, TRRAP knockdown induced cell cycle arrest and increased apoptotic percentages of A2780 sphere cells. Notably, the mRNA levels of stemness-associated markers, that is, OCT4, SOX2, and NANOG, were suppressed in TRRAP-silenced A2780 sphere cells. In addition, TRRAP overexpression increased the mRNA level of NANOG and the transcriptional activity of NANOG promoter in these cells. Furthermore, TRRAP knockdown significantly reduced tumor growth in a murine xenograft transplantation model. Taken together, the findings of the present study suggest that TRRAP plays an important role in the regulation of the proliferation and stemness of ovarian cancer stem cells.

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References

  1. Slotman BJ and Rao BR (1988) Ovarian cancer (review). Etiology, diagnosis, prognosis, surgery, radiotherapy, chemotherapy and endocrine therapy. Anticancer Res 8, 417-434
  2. Aunoble B, Sanches R, Didier E and Bignon YJ (2000) Major oncogenes and tumor suppressor genes involved in epithelial ovarian cancer (review). Int J Oncol 16, 567-576
  3. Cannistra SA (2004) Cancer of the ovary. N Engl J Med 351, 2519-2529 https://doi.org/10.1056/NEJMra041842
  4. Martin LP and Schilder RJ (2009) Management of recurrent ovarian carcinoma: current status and future directions. Semin Oncol 36, 112-125 https://doi.org/10.1053/j.seminoncol.2008.12.003
  5. Kreso A and Dick JE (2014) Evolution of the cancer stem cell model. Cell Stem Cell 14, 275-291 https://doi.org/10.1016/j.stem.2014.02.006
  6. Zhan Q, Wang C and Ngai S (2013) Ovarian cancer stem cells: a new target for cancer therapy. Biomed Res Int 2013, 916819
  7. Burgos-Ojeda D, Rueda BR and Buckanovich RJ (2012) Ovarian cancer stem cell markers: prognostic and therapeutic implications. Cancer Lett 322, 1-7 https://doi.org/10.1016/j.canlet.2012.02.002
  8. Mosca E, Cocola C, Sabour D et al (2010) Overlapping genes may control reprogramming of mouse somatic cells into induced pluripotent stem cells (iPSCs) and breast cancer stem cells. In Silico Biol 10, 207-221
  9. Ben-Porath I, Thomson MW, Carey VJ et al (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40, 499-507 https://doi.org/10.1038/ng.127
  10. Lee M, Nam EJ, Kim SW, Kim S, Kim JH and Kim YT (2012) Prognostic impact of the cancer stem cell-related marker NANOG in ovarian serous carcinoma. Int J Gynecol Cancer 22, 1489-1496 https://doi.org/10.1097/IGJ.0b013e3182738307
  11. Murr R, Vaissiere T, Sawan C, Shukla V and Herceg Z (2007) Orchestration of chromatin-based processes: mind the TRRAP. Oncogene 26, 5358-5372 https://doi.org/10.1038/sj.onc.1210605
  12. Murr R, Loizou JI, Yang YG et al (2006) Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Nat Cell Biol 8, 91-99 https://doi.org/10.1038/ncb1343
  13. Wurdak H, Zhu S, Romero A et al (2010) An RNAi screen identifies TRRAP as a regulator of brain tumor-initiating cell differentiation. Cell Stem Cell 6, 37-47 https://doi.org/10.1016/j.stem.2009.11.002
  14. Charles NA and Holland EC (2010) TRRAP and the maintenance of stemness in gliomas. Cell Stem Cell 6, 6-7 https://doi.org/10.1016/j.stem.2009.12.005
  15. Wang J, Shan M, Liu T et al (2016) Analysis of TRRAP as a Potential Molecular Marker and Therapeutic Target for Breast Cancer. J Breast Cancer 19, 61-67 https://doi.org/10.4048/jbc.2016.19.1.61
  16. McMahon SB, Wood MA and Cole MD (2000) The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Mol Cell Biol 20, 556-562 https://doi.org/10.1128/MCB.20.2.556-562.2000
  17. Nikiforov MA, Chandriani S, Park J et al (2002) TRRAP-dependent and TRRAP-independent transcriptional activation by Myc family oncoproteins. Mol Cell Biol 22, 5054-5063 https://doi.org/10.1128/MCB.22.14.5054-5063.2002
  18. Ichim G, Mola M, Finkbeiner MG, Cros MP, Herceg Z and Hernandez-Vargas H (2014) The histone acetyltransferase component TRRAP is targeted for destruction during the cell cycle. Oncogene 33, 181-192 https://doi.org/10.1038/onc.2012.570
  19. Herceg Z, Hulla W, Gell D et al (2001) Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression. Nat Genet 29, 206-211 https://doi.org/10.1038/ng725
  20. Seo EJ, Kwon YW, Jang IH et al (2016) Autotaxin Regulates Maintenance of Ovarian Cancer Stem Cells through Lysophosphatidic Acid-Mediated Autocrine Mechanism. Stem Cells 34, 551-564 https://doi.org/10.1002/stem.2279
  21. Kim DK, Seo EJ, Choi EJ et al (2016) Crucial role of HMGA1 in the self-renewal and drug resistance of ovarian cancer stem cells. Exp Mol Med 48, e255 https://doi.org/10.1038/emm.2016.73
  22. Choi EJ, Seo EJ, Kim DK et al (2016) FOXP1 functions as an oncogene in promoting cancer stem cell-like characteristics in ovarian cancer cells. Oncotarget 7, 3506-3519
  23. Tapias A, Zhou ZW, Shi Y et al (2014) Trrap-dependent histone acetylation specifically regulates cell-cycle gene transcription to control neural progenitor fate decisions. Cell Stem Cell 14, 632-643 https://doi.org/10.1016/j.stem.2014.04.001
  24. Sawan C, Hernandez-Vargas H, Murr R et al (2013) Histone acetyltransferase cofactor Trrap maintains selfrenewal and restricts differentiation of embryonic stem cells. Stem Cells 31, 979-991 https://doi.org/10.1002/stem.1341
  25. Chen PB, Hung JH, Hickman TL et al (2013) Hdac6 regulates Tip60-p400 function in stem cells. Elife 2, e01557 https://doi.org/10.7554/eLife.01557
  26. Fazzio TG, Huff JT and Panning B (2008) An RNAi screen of chromatin proteins identifies Tip60-p400 as a regulator of embryonic stem cell identity. Cell 134, 162-174 https://doi.org/10.1016/j.cell.2008.05.031
  27. Jeter CR, Liu B, Liu X et al (2011) NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene 30, 3833-3845 https://doi.org/10.1038/onc.2011.114
  28. Wang ML, Chiou SH and Wu CW (2013) Targeting cancer stem cells: emerging role of Nanog transcription factor. Onco Targets Ther 6, 1207-1220
  29. Jeter CR, Yang T, Wang J, Chao HP and Tang DG (2015) Concise Review: NANOG in Cancer Stem Cells and Tumor Development: An Update and Outstanding Questions. Stem Cells 33, 2381-2390 https://doi.org/10.1002/stem.2007
  30. Seo EJ, Kim DK, Jang IH et al (2016) Hypoxia-Notch1-Sox2 signaling is important for maintaining cancer stem cells in ovarian cancer. Oncotarget 7, 55624-55638