Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
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An Epigenetic Mechanism Underlying Doxorubicin Induced EMT in the Human BGC-823 Gastric Cancer Cell

  • Han, Rong-Fei (Department of Immunology, Wuhan University School of Basic Medical Science) ;
  • Ji, Xiang (Department of Immunology, Wuhan University School of Basic Medical Science) ;
  • Dong, Xing-Gao (Department of Immunology, Hubei University for Nationalities) ;
  • Xiao, Rui-Jing (Department of Immunology, Wuhan University School of Basic Medical Science) ;
  • Liu, Yan-Ping (Department of Neurology, Huashan Hospital, Fudan University) ;
  • Xiong, Jie (Department of Immunology, Wuhan University School of Basic Medical Science) ;
  • Zhang, Qiu-Ping (Department of Immunology, Wuhan University School of Basic Medical Science)
  • Published : 2014.05.30
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Abstract

The epithelial to mesenchymal transition (EMT) is a key step during embryonic morphogenesis and plays an important role in drug resistance and metastasis in diverse solid tumors. We previously reported that 48 h treatment of anti-cancer drug doxorubicin could induce EMT in human gastric cancer BGC-823 cells. However, the long term effects of this transient drug treatment were unknown. In this study we found that after 48 h treatment with $0.1{\mu}g/ml$ doxorubicin, most cells died during next week, while a minor population of cells survived and formed colonies. We propagated the surviving cells in drug free medium and found that these long term cultured drug survival cells (abbreviated as ltDSCs) retained a mesenchymal-like cell morphology, and expressed high levels of EMT-related molecules such as vimentin, twist and ${\beta}$-catenin. The expression of chromatin reprogramming factors, Oct4 and c-myc, were also higher in ltDSCs than parental cells. We further demonstrated that the protein level of p300 was upregulated in ltDSCs, and inhibition of p300 by siRNA suppressed the expression of vimentin. Moreover, the ltDSCs had higher colony forming ability and were more drug resistant when compared to parental cells. Our results suggested that an epigenetic mechanism is involved in the EMT of ltDSCs.

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References

  1. Chaffer CL, Brueckmann I, Scheel C, et al (2011). Normal and neoplastic nonstem cells can spontaneously convert to a stemlike state. Proc Natl Acad Sci USA, 108, 7950-5. https://doi.org/10.1073/pnas.1102454108
  2. Garraway LA, Janne PA (2012). Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov, 2, 214-26. https://doi.org/10.1158/2159-8290.CD-12-0012
  3. Han R, Xiong J, Xiao R, et al (2013). Activation of beta-catenin signaling is critical for doxorubicin-induced epithelialmesenchymal transition in BGC-823 gastric cancer cell line. Tumour Biol, 34, 277-84. https://doi.org/10.1007/s13277-012-0548-3
  4. Haslehurst AM, Koti M, et al (2012). EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer, 12, 91. https://doi.org/10.1186/1471-2407-12-91
  5. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013). Cancer drug resistance: an evolving paradigm. Nat Rev Cancer, 13, 714-26. https://doi.org/10.1038/nrc3599
  6. Iyer NG, Ozdag H, Caldas C (2004). p300/CBP and cancer. Oncogene, 23, 4225-31. https://doi.org/10.1038/sj.onc.1207118
  7. Kim MC, Cui FJ, Kim Y (2013). Hydrogen peroxide promotes epithelial to mesenchymal transition and stemness in human malignant mesothelioma cells. Asian Pac J Cancer Prev, 14, 3625-30. https://doi.org/10.7314/APJCP.2013.14.6.3625
  8. Li Y, Zhang X, Polakiewicz RD, Yao TP, Comb MJ (2008). HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization. J Biol Chem, 283, 12686-90. https://doi.org/10.1074/jbc.C700185200
  9. Mak AB, Nixon AM, Kittanakom S, et al (2012). Regulation of CD133 by HDAC6 promotes beta-catenin signaling to suppress cancer cell differentiation. Cell Rep, 2, 951-63. https://doi.org/10.1016/j.celrep.2012.09.016
  10. Sarkar FH, Li Y, Wang Z, Kong D (2009). Pancreatic cancer stem cells and EMT in drug resistance and metastasis. Minerva Chir, 64, 489-500.
  11. Scheel C, Eaton EN, Li SH, et al (2011). Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell, 145, 926-40. https://doi.org/10.1016/j.cell.2011.04.029
  12. Sharma SV, Lee DY, Li B, et al (2010). A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell, 141, 69-80. https://doi.org/10.1016/j.cell.2010.02.027
  13. Shi D, Pop MS, Kulikov R, et al (2009). CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53. Proc Natl Acad Sci USA, 106, 16275-80. https://doi.org/10.1073/pnas.0904305106
  14. Singh A, Settleman J (2010). EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene, 29, 4741-51. https://doi.org/10.1038/onc.2010.215
  15. Suva ML, Riggi N, Bernstein BE (2013). Epigenetic reprogramming in cancer. Science, 339, 1567-70. https://doi.org/10.1126/science.1230184
  16. Wolf D, Rodova M, Miska EA, Calvet JP, Kouzarides T (2002). Acetylation of beta-catenin by CREB-binding protein (CBP). J Biol Chem, 277, 25562-7. https://doi.org/10.1074/jbc.M201196200
  17. Yang J, Weinberg RA (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell, 14, 818-29. https://doi.org/10.1016/j.devcel.2008.05.009
  18. Yang M, Waterman ML, Brachmann RK (2008). hADA2a and hADA3 are required for acetylation, transcriptional activity and proliferative effects of beta-catenin. Cancer Biol Ther, 7, 120-8. https://doi.org/10.4161/cbt.7.1.5197
  19. Zahreddine H, Borden KL (2013). Mechanisms and insights into drug resistance in cancer. Front Pharmacol, 4, 28.
  20. Zhu QC, Gao RY, Wu W, Qin HL (2013). Epithelial-mesenchymal transition and its role in the pathogenesis of colorectal cancer. Asian Pac J Cancer Prev, 14, 2689-98. https://doi.org/10.7314/APJCP.2013.14.5.2689

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