Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
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5-Aza-2'-deoxycytidine Induces Hepatoma Cell Apoptosis via Enhancing Methionine Adenosyltransferase 1A Expression and Inducing S-Adenosylmethionine Production

  • Liu, Wei-Jun (Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University) ;
  • Ren, Jian-Guo (Department of Surgery, Huangshi Fourth Hospital) ;
  • Li, Ting (Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University) ;
  • Yu, Guo-Zheng (Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University) ;
  • Zhang, Jin (Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University) ;
  • Li, Chang-Sheng (Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University) ;
  • Liu, Zhi-Su (Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University) ;
  • Liu, Quan-Yan (Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital, Wuhan University)
  • Published : 2013.11.30
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Abstract

In hepatocellular cancer (HCC), lack of response to chemotherapy and radiation treatment can be caused by a loss of epigenetic modifications of cancer cells. Methionine adenosyltransferase 1A is inactivated in HCC and may be stimulated by an epigenetic change involving promoter hypermethylation. Therefore, drugs releasing epigenetic repression have been proposed to reverse this process. We studied the effect of the demethylating reagent 5-aza-2'-deoxycitidine (5-Aza-CdR) on MAT1A gene expression, DNA methylation and S-adenosylmethionine (SAMe) production in the HCC cell line Huh7. We found that MAT1A mRNA and protein expression were activated in Huh7 cells with the treatment of 5-Aza-CdR; the status of promoter hypermethylation was reversed. At the same time, MAT2A mRNA and protein expression was significantly reduced in Huh7 cells treated with 5-Aza-CdR, while SAMe production was significantly induced. However, 5-Aza-CdR showed no effects on MAT2A methylation. Furthermore, 5-Aza-CdR inhibited the growth of Huh7 cells and induced apoptosis and through down-regulation of Bcl-2, up-regulation of Bax and caspase-3. Our observations suggest that 5-Aza-CdR exerts its anti-tumor effects in Huh7 cells through an epigenetic change involving increased expression of the methionine adenosyltransferase 1A gene and induction of S-adenosylmethionine production.

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References

  1. Ansorena E, Garcia-Trevijano ER, Martinez-Chantar ML, et al (2002). S-adenosylmethionine and methylthioadenosine are anti-apoptotic in cultured rat hepatocytes but pro-apoptotic in human hepatoma cells. Hepatology, 35, 274-80. https://doi.org/10.1053/jhep.2002.30419
  2. Baylin SB, Herman JG, Graff JR, et al (1998). Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res, 72, 141-96.
  3. Cai J, Mao Z, Hwang JJ, et al (1998). Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells. Cancer Res, 58, 1444-50.
  4. Christman JK (2002). 5-Azacytidine and 5-aza-2’-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene, 21, 5483-95. https://doi.org/10.1038/sj.onc.1205699
  5. Fan H, Zhao ZJ, Cheng YC, et al (2007). Gene induction and apoptosis in human hepatocellular carcinoma cells SMMC-7721 exposed to 5-aza-2’-deoxycytidine. Chin Med J, 120, 1626-31.
  6. Frau M, Tomasi ML, Simile MM, et al (2012). Role of transcriptional and posttranscriptional regulation of methionine adenosyltransferases in liver cancer progression. Hepatology, 56, 165-75. https://doi.org/10.1002/hep.25643
  7. Garcia-Manero G (2012). Myelodysplastic syndromes: 2012 update on diagnosis, risk-stratification, and management. Am J Hematol, 87, 692-701. https://doi.org/10.1002/ajh.23264
  8. Huang S, He X (2011). The role of microRNAs in liver cancer progression. Br J Cancer, 104, 235-40. https://doi.org/10.1038/sj.bjc.6606010
  9. Jiang Z, Liang Q, Luo G, et al (2009). HPLC-electrospray tandem mass spectrometry for simultaneous quantitation of eight plasma aminothiols: application to studies of diabetic nephropathy. Talanta, 77, 1279-84. https://doi.org/10.1016/j.talanta.2008.08.031
  10. Jones PL, Wolffe AP (1999). Relationships between chromatin organization and DNA methylation in determining gene expression. Semin Cancer Biol, 9, 339-47. https://doi.org/10.1006/scbi.1999.0134
  11. Krijt J, Duta A, Kozich V (2009). Determination of S-Adenosylmethionine and S-Adenosylhomocysteine by LC-MS/MS and evaluation of their stability in mice tissues. J Chromatogr B Analyt Technol Biomed Life Sci, 877, 2061-6. https://doi.org/10.1016/j.jchromb.2009.05.039
  12. Lee S, Lee HJ, Kim JH, et al (2003). Aberrant CpG island methylation along multistep hepatocarcinogenesis. Am J Pathol, 163, 1371-8. https://doi.org/10.1016/S0002-9440(10)63495-5
  13. Li J, Ramani K, Sun Z, et al (2010). Forced expression of methionine adenosyltransferase 1A in human hepatoma cells suppresses in vivo tumorigenicity in mice. Am J Pathol, 176, 2456-66. https://doi.org/10.2353/ajpath.2010.090810
  14. Liu LH, Xiao WH, Liu WW (2001). Effect of 5-2Aza-2’-deoxycytidine on the P16 tumor suppressor gene in hepatocellular carcinoma cell line HepG2. World J Gastroenterol, 7, 131-5. https://doi.org/10.3748/wjg.v7.i1.131
  15. Lu SC, Mato JM (2008). S-Adenosylmethionine in cell growth, apoptosis and liver cancer. J Gastroenterol Hepatol, 23, S73-7. https://doi.org/10.1111/j.1440-1746.2007.05289.x
  16. Lu SC, Ramani K, Ou X, et al (2009). S-adenosylmethionine in the chemoprevention and treatment of hepatocellular carcinoma in a rat model. Hepatology, 50, 462-71. https://doi.org/10.1002/hep.22990
  17. Martinez-Chantar ML, Vazquez-Chantada M, Garnacho-Echevarria M, et al (2006). S-Adenosylmethionine regulates cytoplasmic HuR via AMP-activated kinase. Gastroenterology, 131, 223-32. https://doi.org/10.1053/j.gastro.2006.04.019
  18. Markham GD, Pajares MA (2009). Structure-function relationships in methionine adenosyltransferases. Cell Mol Life Sci, 66, 636-48. https://doi.org/10.1007/s00018-008-8516-1
  19. Mato JM, Lu SC (2007). Role of S-adenosyl-L-methionine in liver health and injury. Hepatology, 45, 1306-12. https://doi.org/10.1002/hep.21650
  20. Mato JM, Martinez-Chantar ML, Lu SC (2008). Methionine metabolism and liver disease. Annu Rev Nutr, 28, 273-93. https://doi.org/10.1146/annurev.nutr.28.061807.155438
  21. Tao SF, Zhang CS, Guo XL, et al (2012). Anti-tumor effect of 5-aza-2’-deoxycytidine by inhibiting telomerase activity in hepatocellular carcinoma cells. World J Gastroenterol, 18, 2334-43. https://doi.org/10.3748/wjg.v18.i19.2334
  22. Tazi J, Bird A (1990). Alternative chromatin structure at CpG islands. Cell, 60, 909-20. https://doi.org/10.1016/0092-8674(90)90339-G
  23. Torres L, Avila MA, Carretero MV, et al (2000). Liver-specific methionine adenosyltransferase MAT1A gene expression is associated with a specific pattern of promoter methylation and histone acetylation: implications for MAT1A silencing during transformation. FASEB J, 14, 95-102. https://doi.org/10.1096/fasebj.14.1.95
  24. Ueki T, Toyota M, Sohn T, et al (2000). Methylation of multiple genes in pancreatic adenocarcinoma. Cancer Res, 60, 1835-9.
  25. Villanueva A, Llovet JM (2011). Targeted therapies for hepatocellular carcinoma. Gastroenterology, 140, 1410-26. https://doi.org/10.1053/j.gastro.2011.03.006
  26. Wang D, Liu Z, Liu Q, et al (2011). The relationship between HBx and methylation status of MATs’promoters in hepatocellular carcinoma. Chin J Exp Surg, 28, 242-4.
  27. Watanabe Y, Maekawa M (2010). Methylation of DNA in cancer. Adv Clin Chem, 52, 145-67. https://doi.org/10.1016/S0065-2423(10)52006-7
  28. Xie GS, Hou AR, Li LY, et al (2006). Aberrant p16 promoter methylation in bronchial mucosae as a biomarker for the early detection of lung cancer. Chin Med J, 119, 1469-72.
  29. Yang H, Huang ZZ, Zeng Z, et al (2001). Role of promoter methylation in increased methionine adenosyltransferase 2A expression in human liver cancer. Am J Physiol Gastrointest Liver Physiol, 280, 184-90. https://doi.org/10.1152/ajpgi.2001.280.2.G184
  30. Yang H, Sadda MR, Li M , et al (2004). S-adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl-x (S). Hepatology, 40, 221-31. https://doi.org/10.1002/hep.20274
  31. Zhang J, Gong C, Bing Y, et al (2013). Hypermethylation-repressed methionine adenosyltransferase 1A as a potential biomarker for hepatocellular carcinoma. Hepatol Res, 43, 374-83. https://doi.org/10.1111/j.1872-034X.2012.01099.x

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