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SAHA Inhibits the Growth of Colon Tumors by Decreasing Histone Deacetylase and the Expression of Cyclin D1 and Survivin

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Pathology & Oncology Research

Abstract

We studied the effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, on colon cancer. The expression of HDACs in colorectal cancer specimens and the effects of SAHA on colon cancer cells and tumors of nude mice were assessed. Treatment with SAHA (3 μm) for 72 h induced downregulation of different subtypes of HDAC proteins and also induced acetylation of histone 3 and histone 4. SAHA significantly inhibited the expression of the oncogenic protein c-myc and also increased the expression of the p53 and Rb proteins. The immunohistochemical staining of HDACs, including HDAC1, HDAC2, HDAC3, and HDAC4, was significantly increased in colorectal adenocarcinoma specimens compared to healthy control tissues. In addition, murine studies showed that 100 mg/kg SAHA administered by intraperitoneal injection significantly induced tumor necrosis and inhibited the growth of colon tumors. Immunohistochemistry of the tumor tissues from nude mice revealed that SAHA inhibited the expression of different subtypes of histone deacetylase, the anti-apoptotic proteins cyclin D1, survivin, and also inhibited cell proliferative as determined by Ki67 expression. SAHA inhibited the growth of colon tumors by decreasing histone deacetylases and the expression of cyclin D1 and survivin in nude mice.

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References

  1. Mayer RJ (2009) Targeted therapy for advanced colorectal cancer-more is not always better. N Eng J Med 360:623–625

    Article  CAS  Google Scholar 

  2. Wilko W, Annika R, Silvia N, Aurelia N, Ann-Christin B, Manfred D, Volker G, Boehm M, Thomas B, Carsten D (2008) Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: specific role of class I histone deacetylases in vitro and in vivo. Clin Cancer Res 14:1669–1677

    Article  Google Scholar 

  3. Ito K, Adcock IM (2002) Histone acetylation and histone deacetylation. Mol Biotechnol 20:99–106

    Article  PubMed  CAS  Google Scholar 

  4. Kuo MH, Allis CD (1998) Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays 20:615–626

    Article  PubMed  CAS  Google Scholar 

  5. Kim DH, Kim M, Kwon HJ (2003) Histone deacetylase in carcinogenesis and its inhibitors as anti-cancer agents. J Biochem Mol Biol 36:110–119

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  7. Luong QT, O’Kelly J, Braunstein GD, Hershman JM, Koeffler HP (2006) Antitumor activity of suberoylanilide hydroxamic acid against thyroid cancer cell lines in vitro and in vivo. Clin Cancer Res 12:5570–5577

    Article  PubMed  CAS  Google Scholar 

  8. Sun PC, Tzao C, Chen BH, Liu CW, Yu CP, Jin JS (2010) Suberoylanilide hydroxamic acid induces apoptosis and sub-G1 arrest of 320 HSR colon cancer cells. J Biochem Sci 17:76–85

    CAS  Google Scholar 

  9. Jin JS, Hsieh DS, Loh SH, Chen A, Yao CW, Yen CY (2006) Increasing expression of serine protease matriptase in ovary tumors: tissue microarray analysis of immunostaining score with clinicopathological parameters. Mod Pathol 19:447–452

    Article  PubMed  CAS  Google Scholar 

  10. Jin JS, Wu WY, Lin YF (2006) Higher expression of epidermal growth factor receptor is associated with extracellular matrix metalloprotease inducer in colorectal adenocarcinoma: tissue microarray analysis of immunostaining score with clinicopathological parameters. Dis Markers 22:309–316

    PubMed  CAS  Google Scholar 

  11. Jung M (2001) Inhibitors of histone deacetylase as new anticancer agents. Curr Med Chem 8:1505–1511

    PubMed  CAS  Google Scholar 

  12. Lindemann RK, Gabrielli B, Johnstone RW (2004) Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle 3:779–788

    Article  PubMed  CAS  Google Scholar 

  13. Truchet I, Jozan S, Baron S (2008) Estrogen and antiestrogen-dependent regulation of breast cancer cell proliferation in multicellular spheroids: Influence of cell microenvironment. Int J Oncol 32:1033–1039

    PubMed  CAS  Google Scholar 

  14. Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6:38–51

    Article  PubMed  CAS  Google Scholar 

  15. Alessandro V, Cinzia V, Gessica F, Elena CC, Mirko B, Debora R, Prasun C, Chantal P, Raffaele DF, Paola G, Christian S, Stefania DM (2004) Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. PNAS 101:15064–15069

    Article  Google Scholar 

  16. Wang S, Yan-Neale Y, Cai R, Alimov I, Cohen D (2006) Activation of mitochondrial pathway is crucial for tumor selective induction of apoptosis by LAQ824. Cell Cycle 5:1662–1668

    Article  PubMed  CAS  Google Scholar 

  17. Zbar AP, Kennedy PJ, Singh V (2009) Functional outcome following restorative rectal cancer surgery. Acta Chir Iugosl 56:9–16

    Article  PubMed  CAS  Google Scholar 

  18. Kelly WK, O’Connor OA, Krug LM (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23:3923–3931

    Article  PubMed  CAS  Google Scholar 

  19. Sakajiri S, Kumagai T, Kawamata N, Saitoh T, Said JW, Koeffler HP (2005) Histone deacetylase inhibitors profoundly decrease proliferation of human lymphoid cancer cell lines. Exp Hematol 33:53–61

    Article  PubMed  CAS  Google Scholar 

  20. Bali P, Pranpat M, Swaby R (2005) Activity of suberoylanilide hydroxamic acid against human breast cancer cells with amplification of Her-2. Clin Cancer Res 11:6382–6389

    Article  PubMed  CAS  Google Scholar 

  21. Rundall BK, Denlinger CE, Jones DR (2005) Suberoylanilide hydroxamic acid combined with gemcitabine enhances apoptosis in non-small cell lung cancer. Surgery 138:360–367

    Article  PubMed  Google Scholar 

  22. Takai N, Desmond JC, Kumagai T (2004) Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells. Clin Cancer Res 10:1141–1149

    Article  PubMed  CAS  Google Scholar 

  23. Takai N, Kawamata N, Gui D, Said JW, Miyakawa I, Koeffler HP (2004) Human ovarian carcinoma cells: histone deacetylase inhibitors exhibit antiproliferative activity and potently induce apoptosis. Cancer 101:2760–2770

    Article  PubMed  CAS  Google Scholar 

  24. Altieri DC (2006) The case for survivin as a regulator of microtubule dynamics and cell-death decisions. Curr Opin Cell Biol 18:609–615

    Article  PubMed  CAS  Google Scholar 

  25. Noh EJ, Lim DS, Jeong G, Lee JS (2009) An HDAC inhibitor, trichostatin A, induces a delay at G2/M transition, slippage of spindle checkpoint, and cell death in a transcription-dependent manner. Biochem Biophys Res Commun 378:326–331

    Article  PubMed  CAS  Google Scholar 

  26. Kim DH, Kundu JK, Surh YJ (2011) Redox modulation of p53: mechanisms and functional significance. Mol Carcinog 50:222–234

    Article  PubMed  CAS  Google Scholar 

  27. Shen F, Kirmani KZ, Xiao Z, Thirlby BH, Hickey RJ, Malkas LH (2011) Nuclear protein isoforms: implications for cancer diagnosis and therapy. J Cell Biochem 112:756–760

    Article  PubMed  CAS  Google Scholar 

  28. Smith RA, Tang J, Tudur-Smith C, Neoptolemos JP, Ghaneh P (2011) Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer. Br J Cancer 104:1440–1451

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by a grant from the Tri-Service General Hospital (TSGH-C100-007-009-10-S04), R. O. C.

Declaration of competing interests

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Pathology, Tungs’ Taichung MetroHarbor Hospital, Wuqi Township, Taichung County, Taiwan, Republic of China

    Jong-Shiaw Jin & Tang-Yi Tsao

  2. Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei County, Taiwan, Republic of China

    Pei-Chang Sun & Cheng-Ping Yu

  3. Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Kung Road, Neihu, 114, Taipei County, Taiwan, Republic of China

    Ching Tzao

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  1. Jong-Shiaw Jin
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  2. Tang-Yi Tsao
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  3. Pei-Chang Sun
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  4. Cheng-Ping Yu
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  5. Ching Tzao
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Correspondence to Ching Tzao.

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Jin, JS., Tsao, TY., Sun, PC. et al. SAHA Inhibits the Growth of Colon Tumors by Decreasing Histone Deacetylase and the Expression of Cyclin D1 and Survivin. Pathol. Oncol. Res. 18, 713–720 (2012). https://doi.org/10.1007/s12253-012-9499-7

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  • DOI: https://doi.org/10.1007/s12253-012-9499-7

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