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

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

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.

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Acknowledgment

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

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Authors and Affiliations

  1. Institute of Pathology, Technische Universität München, Munich, Germany

    Kathrin Mutze, Rupert Langer MD, Karen Becker MD, Birgit Luber PhD, Heinz Höfler MD & Gisela Keller PhD

  2. Department of Surgery, University Heidelberg, Heidelberg, Germany

    Katja Ott MD

  3. Department of Surgery, Technische Universität München, Munich, Germany

    Alexander Novotny MD

  4. Medical Statistics and Epidemiology, Technische Universität München, Munich, Germany

    Alexander Hapfelmeier

  5. Institute of Toxicology, Helmholtz-Zentrum München, Oberschleissheim, Germany

    Martin Göttlicher MD

  6. Institute of Pathology, Helmholtz-Zentrum München, Oberschleissheim, Germany

    Heinz Höfler MD

Authors
  1. Kathrin Mutze
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  2. Rupert Langer MD
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  3. Karen Becker MD
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  4. Katja Ott MD
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  7. Alexander Hapfelmeier
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  8. Martin Göttlicher MD
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  9. Heinz Höfler MD
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  10. Gisela Keller PhD
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Corresponding author

Correspondence to Gisela Keller PhD.

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Supplementary material 1 (DOC 28 kb)

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)

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Mutze, K., Langer, R., Becker, K. et al. Histone Deacetylase (HDAC) 1 and 2 Expression and Chemotherapy in Gastric Cancer. Ann Surg Oncol 17, 3336–3343 (2010). https://doi.org/10.1245/s10434-010-1182-1

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  • DOI: https://doi.org/10.1245/s10434-010-1182-1

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