Annals of Surgical Oncology

, Volume 17, Issue 12, pp 3336–3343 | Cite as

Histone Deacetylase (HDAC) 1 and 2 Expression and Chemotherapy in Gastric Cancer

  • Kathrin Mutze
  • Rupert Langer
  • Karen Becker
  • Katja Ott
  • Alexander Novotny
  • Birgit Luber
  • Alexander Hapfelmeier
  • Martin Göttlicher
  • Heinz Höfler
  • Gisela Keller
Translational Research and Biomarkers

Abstract

Background

Histone deacetylases (HDACs) modulate chromatin and may influence the effect of DNA-damaging drugs. We investigated HDAC1 and -2 expression in gastric carcinomas (GCs) for an association of patient outcome with conventional neoadjuvant chemotherapy. In vitro, HDAC inhibitors were evaluated as alternative treatment options.

Methods

HDAC1/2 expression was analyzed immunohistochemically in 127 pretherapeutic biopsy samples of neoadjuvant (platinum/5-fluorouracil) chemotherapy-treated GC patients and correlated with response and overall survival (OS). Chemosensitivity of four GC cell lines to cisplatin and the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) and valproic acid was determined by XTT assays. Efficiencies of combined drug schedules were analyzed.

Results

High expression of HDAC1/2 was found in 69 (54%) of 127 and 108 (85%) of 127 carcinomas, respectively, and was not associated with response or OS. In patients whose disease responded to therapy, high HDAC1 expression was associated with worse OS (P = 0.005). In cell lines, sequential treatment with SAHA and cisplatin showed synergistic effects irrespective of the initial cisplatin sensitivity.

Conclusions

HDAC1 and -2 expression is not suitable to predict response or survival for neoadjuvant-treated GC patients, but HDAC1 expression may be used for risk stratification in patients whose disease responds to therapy. Sequential treatment with SAHA and cisplatin may represent an alternative treatment option for GC patients.

Keywords

Gastric Cancer Overall Survival Gastric Cancer Patient HDAC Inhibitor Gastric Cancer Cell Line 

Notes

Acknowledgment

This work was supported by the Wilhelm-Sander-Stiftung (grant 2006.035-1 to G.K. and K.O.).

Supplementary material

10434_2010_1182_MOESM1_ESM.doc (28 kb)
Supplementary material 1 (DOC 28 kb)
10434_2010_1182_MOESM2_ESM.eps (7.4 mb)
Supplementary Fig. 1 (a) Expression of HDAC1 in cell pellets of MKN28, MKN45, AGS and KATOIII cells determined by immunohistochemistry is shown. Original magnification 1:400 (b) Western blot analysis of HDAC1 expression in cell lysates. β-actin expression served as loading control (c) Densitometric analysis of the HDAC1 expression normalised to β-actin expression levels Supplementary material 2 (EPS 7591 kb)

References

  1. 1.
    Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20.CrossRefPubMedGoogle Scholar
  2. 2.
    Lordick F, Siewert JR. Recent advances in multimodal treatment for gastric cancer: a review. Gastric Cancer. 2005;8:78–85.CrossRefPubMedGoogle Scholar
  3. 3.
    Glozak MA, Seto E. Histone deacetylases and cancer. Oncogene. 2007;26:5420–32.CrossRefPubMedGoogle Scholar
  4. 4.
    Kristensen LS, Nielsen HM, Hansen LL. Epigenetics and cancer treatment. Eur J Pharmacol. 2009;625:131–42.CrossRefPubMedGoogle Scholar
  5. 5.
    Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–92.CrossRefPubMedGoogle Scholar
  6. 6.
    Napieralski R, Ott K, Kremer M, et al. Methylation of tumor-related genes in neoadjuvant-treated gastric cancer: relation to therapy response and clinicopathologic and molecular features. Clin Cancer Res. 2007;13:5095–102.CrossRefPubMedGoogle Scholar
  7. 7.
    Kim MS, Blake M, Baek JH, et al. Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res. 2003;63:7291–300.PubMedGoogle Scholar
  8. 8.
    Lin CT, Lai HC, Lee HY, et al. Valproic acid resensitizes cisplatin-resistant ovarian cancer cells. Cancer Sci. 2008;99:1218–26.CrossRefPubMedGoogle Scholar
  9. 9.
    Davies NP, Hardman LC, Murray V. The effect of chromatin structure on cisplatin damage in intact human cells. Nucleic Acids Res. 2000;28:2954–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Weichert W, Roske A, Gekeler V, et al. Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis. Lancet Oncol. 2008;9:139–48.CrossRefPubMedGoogle Scholar
  11. 11.
    Weichert W, Roske A, Niesporek S, et al. 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. 2008;14:1669–77.CrossRefPubMedGoogle Scholar
  12. 12.
    Suzuki J, Chen YY, Scott GK, et al. Protein acetylation and histone deacetylase expression associated with malignant breast cancer progression. Clin Cancer Res. 2009;15:3163–71.CrossRefPubMedGoogle Scholar
  13. 13.
    Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006;6:38–51.CrossRefPubMedGoogle Scholar
  14. 14.
    Schuhmacher CP, Fink U, Becker K, et al. Neoadjuvant therapy for patients with locally advanced gastric carcinoma with etoposide, doxorubicin, and cisplatinum. Closing results after 5 years of follow-up. Cancer. 2001;91:918–27.CrossRefPubMedGoogle Scholar
  15. 15.
    Ott K, Sendler A, Becker K, et al. Neoadjuvant chemotherapy with cisplatin, 5-FU, and leucovorin (PLF) in locally advanced gastric cancer: a prospective phase II study. Gastric Cancer. 2003;6:159–67.CrossRefPubMedGoogle Scholar
  16. 16.
    Ott K, Fink U, Becker K, et al. Prediction of response to preoperative chemotherapy in gastric carcinoma by metabolic imaging: results of a prospective trial. J Clin Oncol. 2003;21:4604–10.CrossRefPubMedGoogle Scholar
  17. 17.
    Stocker G, Ott K, Henningsen N, et al. CyclinD1 and interleukin-1 receptor antagonist polymorphisms are associated with prognosis in neoadjuvant-treated gastric carcinoma. Eur J Cancer. 2009;45:3326–35.CrossRefPubMedGoogle Scholar
  18. 18.
    Becker K, Mueller JD, Schulmacher C, et al. Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer. 2003;98:1521–30.CrossRefPubMedGoogle Scholar
  19. 19.
    Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27–55.CrossRefPubMedGoogle Scholar
  20. 20.
    Gyorffy B, Surowiak P, Kiesslich O, et al. Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006;118:1699–712.CrossRefPubMedGoogle Scholar
  21. 21.
    Kelly WK, Richon VM, O’Connor O, et al. Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res. 2003;9:3578–88.PubMedGoogle Scholar
  22. 22.
    Fritzsche FR, Weichert W, Roske A, et al. Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer. BMC Cancer. 2008;8:381.Google Scholar
  23. 23.
    Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5:275–84.CrossRefPubMedGoogle Scholar
  24. 24.
    Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet. 2006;7:21–33.CrossRefPubMedGoogle Scholar
  25. 25.
    Zhu P, Martin E, Mengwasser J, et al. Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell. 2004;5:455–63.CrossRefPubMedGoogle Scholar
  26. 26.
    Lee JH, Park JH, Jung Y, et al. Histone deacetylase inhibitor enhances 5-fluorouracil cytotoxicity by down-regulating thymidylate synthase in human cancer cells. Mol Cancer Ther. 2006;5:3085–95.CrossRefPubMedGoogle Scholar
  27. 27.
    Owonikoko TK, Ramalingam SS, Kanterewicz B, et al. Vorinostat increases carboplatin and paclitaxel activity in non–small cell lung cancer cells. Int J Cancer. 126:743–55.Google Scholar
  28. 28.
    Zhang X, Yashiro M, Ren J, Hirakawa K. Histone deacetylase inhibitor, trichostatin A, increases the chemosensitivity of anticancer drugs in gastric cancer cell lines. Oncol Rep. 2006;16:563–8.PubMedGoogle Scholar
  29. 29.
    Gorisch SM, Wachsmuth M, Toth KF, et al. Histone acetylation increases chromatin accessibility. J Cell Sci. 2005;118:5825–34.CrossRefPubMedGoogle Scholar
  30. 30.
    Dejligbjerg M, Grauslund M, Litman T, et al. Differential effects of class I isoform histone deacetylase depletion and enzymatic inhibition by belinostat or valproic acid in HeLa cells. Mol Cancer. 2008;7:70.Google Scholar

Copyright information

© Society of Surgical Oncology 2010

Authors and Affiliations

  • Kathrin Mutze
    • 1
  • Rupert Langer
    • 1
  • Karen Becker
    • 1
  • Katja Ott
    • 2
  • Alexander Novotny
    • 3
  • Birgit Luber
    • 1
  • Alexander Hapfelmeier
    • 4
  • Martin Göttlicher
    • 5
  • Heinz Höfler
    • 1
    • 6
  • Gisela Keller
    • 1
  1. 1.Institute of PathologyTechnische Universität MünchenMunichGermany
  2. 2.Department of SurgeryUniversity HeidelbergHeidelbergGermany
  3. 3.Department of SurgeryTechnische Universität MünchenMunichGermany
  4. 4.Medical Statistics and EpidemiologyTechnische Universität MünchenMunichGermany
  5. 5.Institute of ToxicologyHelmholtz-Zentrum MünchenOberschleissheimGermany
  6. 6.Institute of PathologyHelmholtz-Zentrum MünchenOberschleissheimGermany

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