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Mechanism of histone deacetylase inhibitor Trichostatin A induced apoptosis in human osteosarcoma cells

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Abstract

Although histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in malignancy, how they exert their effect on osteosarcoama cells is as yet unclear. This study was undertaken to investigate the underlying mechanism of a HDAC inhibitor Trichostatin A (TSA)-induced apoptosis in a osteosarcoma cell line HOS. We observed that TSA treatment decreased the viability of the cells and prominently increased acetylation of histone H3. Evidence was obtained indicating that TSA induced apoptosis of HOS cells as follows: (1) Generation of DNA fragmentation; (2) activation of procaspase-3; (3) cleavage of PARP; and (4) increase of DNA hypoploidy. The reduction of MMP and the release of cytochrome c to cytosol were also shown, indicating that TSA induces apoptosis in HOS cells in a histone acetylation- and mitochondria-dependent fashions. We also examined whether TSA can sensitize HOS cells to the action of an antitumor agent genistein. The combination therapy of TSA and genistein showed synergistic anticancer effect indicating that TSA can be considered as a novel therapeutic strategy for osteosarcoma not only from its direct apoptosis-inducing activity but also from the possibility of sensitization to other antitumor agents.

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References

  1. Lee Y, Hayes J, Pruss, Wolffe P. A positive role for histone acetylation in transcription factor access to nucleosomal DNA. Cell 1993; 72: 73–84.

    Article  PubMed  Google Scholar 

  2. Wolffe P, Guschin. Chromatin structural features and targets that regulate transcription. J Struct Biol 2000; 129: 102–122.

  3. Weidle H, Grossmann A,.Inhibition of histone deacetylases: Anew strategy to target epigenetic modifications for anticancer treatment. Anticancer Res 2000; 20: 1127-1132}.

    Google Scholar 

  4. Narlikar J, Fan HY, Kingston RE. Cooperation between complexes that regulate chromatin structure and transcription. Cell 2002; 108: 475–487.

    Article  PubMed  Google Scholar 

  5. Loidl P, Grobner P. Postsynthetic acetylation of histones during the cell cycle: A general function for the displacement of histones during chromatin rearrangements. Nucleic Acids Res 1987; 15: 8351–8366.

    PubMed  Google Scholar 

  6. Marks PA, Richon VM, Breslow R, Rifkind RA. Histone deacetylase inhibitors as new cancer drugs. Curr Opin Oncol 2001; 13: 477–483.

    Google Scholar 

  7. Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: Induces of differentiation or apoptosis of transformed cells. J Natl Cancer Inst2000; 92: 1210–1216.

    Article  PubMed  Google Scholar 

  8. Fuchs B, Pritchard DJ. Etiology of osteosarcoma. Clin Orthop 2002; 397: 40–52.

    Article  PubMed  Google Scholar 

  9. Bruland OS, Phil A. On the current management of osteosarcoma. A critical evaluation and a proposal for a modified treatment strategy. Eur J Cancer1997; 33: 1725–1731.

    Article  PubMed  Google Scholar 

  10. Sowa Y, Orita T, Minamikawa S, et al. Histone deacetylase inhibitor activates theWAF1/Cip1 gene romoter through the Sp1 sites. Biochem Biophys Res Commun 1997; 241: 142–150.

    Article  PubMed  Google Scholar 

  11. Hirose T, Sowa Y, Takahashi S, et al. p53-independent induction of Gadd45 by histone deacetylase inhibitor: Coordinate regulation by transcription factors Oct-1 and NF-Y. Oncogene 2003; 22: 7762–7773.

    Article  PubMed  Google Scholar 

  12. Marks PA, Rifkind RA. Erythroleukemic differentiation. Annu Rev Biochem 1978; 47: 419–448.

    Article  PubMed  Google Scholar 

  13. Hoshikawa Y, Kwon HJ, Yoshida M, Horinouchi S, Beppu T. Trichostatin A induces morphological changes and gelsolin expression by inhibiting histone deacetylase in human carcinoma cell lines. Exp Cell Res 1994; 214: 189–197.

    Article  PubMed  Google Scholar 

  14. Van Lint C, Emiliani S, Verdin E. The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr1996; 5: 245–253.

    PubMed  Google Scholar 

  15. Saito A, Yamashita T, Mariko Y, et al. A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc Natl Acad Sci USA 1999; 96: 4592–4597.

    Article  PubMed  Google Scholar 

  16. Kim MS, Kwon HJ, Lee YM, et al. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 2001; 7: 437–443.

    Article  PubMed  Google Scholar 

  17. Kwon HJ, Kim MS, Kim MJ, Nakajima H, Kim KW. Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis. Int J Cancer 2002; 97: 290–296.

    Article  PubMed  Google Scholar 

  18. Deroanne CF, Bonjean K, Servotte S, et al. Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 2002; 21: 427–436.

    Article  PubMed  Google Scholar 

  19. Stossi F, Barnett DH, Frasor J, Komm B, Lyttle CR, Katzenellenbogen BS. Transcriptional profiling of estrogenregulated gene expression via estrogen receptor alpha or estrogen receptor ta in human osteosarcoma cells: Distinct and common target genes for these receptors. Endocrinology 2004; [Epub ahead of print].

  20. Park BS, Baek SJ, Song KH, et al. Genistein-induced apoptosis of p815 mastocytoma cells is mediated by Bax and augmented by a proteasome inhibitor, lactacystin. Nutr Cancer 2002; 42: 248–255.

    Article  PubMed  Google Scholar 

  21. Farhan H, Cross HS. Transcriptional inhibition of CYP24 by genistein. Ann NY Acad Sci 2002; 973: 459–462.

    PubMed  Google Scholar 

  22. Morabito N, Crisafulli A, Vergara C, et al. Effects of genisteinand hormonereplacement therapy on bone loss in early postmenopausal women: A randomized double-blind placebocontrolled study. J Bone Miner Res 2002; 17: 1904–1912.

    PubMed  Google Scholar 

  23. Medema RH, Herrera RE, Lam F, Weinberg RA. Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc Natl Acad Sci USA 1995; 92: 6289–6293.

    PubMed  Google Scholar 

  24. Liggett WH Jr, Sewell DA, Rocco J, et al. p16 and p16 beta are potent growth suppressors of head and neck squamous carcinoma cells in vitro. Cancer Res 1996; 56: 4119–4123.

    PubMed  Google Scholar 

  25. Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 1995; 83: 993–1000.

    Article  PubMed  Google Scholar 

  26. Stott FJ, Bates S, James MC, et al. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J 1998; 17: 5001–5014.

    Article  PubMed  Google Scholar 

  27. Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1998; 92: 725–734.

    Article  PubMed  Google Scholar 

  28. Richon VM, Webb Y, Merger R, et al. Second generation hybrid polar compounds are potent inducers of transformed cell differentiation. Proc Natl Acad Sci USA 1996; 93: 5705–5708.

    Article  PubMed  Google Scholar 

  29. Xiao H, Hasegawa T, Isobe K. Both Sp1 and Sp3 are responsible for p21waf1 promoter activity induced by histone deacetylase inhibitor in NIH3T3 cells. J Cell Biochem 1999; 73: 291–302.

    Article  PubMed  Google Scholar 

  30. DiGiuseppe JA, Weng LJ, Yu KH, et al. Phenylbutyrateinduced G1 arrest and apoptosis in myeloid leukemia cells: Structure-function analysis. Leukemia 1999; 13: 1243–1253.

    Article  PubMed  Google Scholar 

  31. Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA 2000; 97: 10014–10019.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute of Cell Death and Differentiation, Dong-A University College of Medicine (BK21 program) and Medical Science Research Center, Busan, 602-714, South Korea

    M. S. Roh, J. H. Jeong, H. C. Kwon, D. J. Suh, S.-B. Yee & Y. H. Yoo

  2. Department of Oral Anatomy and Cell Biology, Pusan National University College of Dentistry, Busan, 602-739, South Korea

    C. W. Kim, B. S. Park & G. C. Kim

  3. Department of Cardiothoracic Surgery, College of Medicine, Inje University, Busan, 633-165, South Korea

    K. H. Cho

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  1. M. S. Roh
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  2. C. W. Kim
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  3. B. S. Park
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  4. G. C. Kim
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  5. J. H. Jeong
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  6. H. C. Kwon
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  7. D. J. Suh
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  8. K. H. Cho
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  9. S.-B. Yee
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  10. Y. H. Yoo
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Correspondence to Y. H. Yoo.

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Roh, M.S., Kim, C.W., Park, B.S. et al. Mechanism of histone deacetylase inhibitor Trichostatin A induced apoptosis in human osteosarcoma cells. Apoptosis 9, 583–589 (2004). https://doi.org/10.1023/B:APPT.0000038037.68908.6e

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  • DOI: https://doi.org/10.1023/B:APPT.0000038037.68908.6e

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