Skip to main content
SpringerLink
Log in

Clinical significance of histone deacetylases 1, 2, 3, and 7: HDAC2 is an independent predictor of survival in HCC

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Histone deacetylases (HDAC) are responsible for the transcriptional control of genes through chromatin remodeling and control tumor suppressor genes. In several tumors, their expression has been linked to clinicopathological factors and patient survival. This study investigates HDACs 1, 2, 3, and 7 expressions in hepatocellular carcinoma (HCC) and their correlation with clinical data and patient survival. Tissue microarrays of 170 surgically resected primary HCCs and adjacent uninvolved tissue were evaluated immunohistochemically for the expression of HDACs 1, 2, 3, 7, and Ki-67 and were analyzed with respect to clinicopathological data and patient survival. HDACs 1, 2, 3, and Ki-67 were expressed significantly higher in cancer cells compared to normal tissue (HDAC1: p = 0.034, HDACs 2 and 3 and Ki-67: p < 0.001), while HDAC7 expression did not differ between HCC and non-cancerous liver tissue. In tumor tissue HDACs 1–3 expression levels showed high concordance with each other, Ki-67 and tumor grade (p < 0.001). High HDAC2 expression was associated with poor survival in low-grade and early-stage tumors (p < 0.05). The expression of the HDACs 1, 2, and 3 (but not HDAC7) isoenzymes correlates with clinicopathological factors, and HDAC2 expression has an impact on patient survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bosch FX, Ribes J, Cleries R, Diaz M (2005) Epidemiology of hepatocellular carcinoma. Clin Liver Dis 9(2):191–211

    Article  PubMed  Google Scholar 

  2. Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362(9399):1907–1917

    Article  PubMed  Google Scholar 

  3. Okamoto K, Neureiter D, Ocker M (2009) Biomarkers for novel targeted therapies of hepatocellular carcinoma. Histol Histopathol 24(4):493–502

    PubMed  CAS  Google Scholar 

  4. Greten TF, Korangy F, Manns MP, Malek NP (2009) Molecular therapy for the treatment of hepatocellular carcinoma. Br J Canc 100(1):19–23

    Article  CAS  Google Scholar 

  5. Finn RS (2010) Development of molecularly targeted therapies in hepatocellular carcinoma: where do we go now? Clin Canc Res 16(2):390–397

    Article  CAS  Google Scholar 

  6. Ocker M, Schneider-Stock R (2007) Histone deacetylase inhibitors: signalling towards p21cip1/waf1. Int J Biochem Cell Biol 39(7–8):1367–1374

    Article  PubMed  CAS  Google Scholar 

  7. Ocker M (2010) Deacetylase inhibitors-focus on non-histone targets and effects. World J Biol Chem 1(5):55–61

    Article  PubMed  Google Scholar 

  8. Di Fazio P, Schneider-Stock R, Neureiter D, Okamoto K, Wissniowski T, Gahr S, Quint K, Meissnitzer M, Alinger B, Montalbano R, Sass G, Hohenstein B, Hahn EG, Ocker M (2010) The pan-deacetylase inhibitor panobinostat inhibits growth of hepatocellular carcinoma models by alternative pathways of apoptosis. Cell Oncol 32(4):285–300

    PubMed  Google Scholar 

  9. Gahr S, Peter G, Wissniowski TT, Hahn EG, Herold C, Ocker M (2008) The histone-deacetylase inhibitor MS-275 and the CDK-inhibitor CYC-202 promote anti-tumor effects in hepatoma cell lines. Oncol Rep 20(5):1249–1256

    PubMed  CAS  Google Scholar 

  10. Ocker M, Alajati A, Ganslmayer M, Zopf S, Luders M, Neureiter D, Hahn EG, Schuppan D, Herold C (2005) The histone-deacetylase inhibitor SAHA potentiates proapoptotic effects of 5-fluorouracil and irinotecan in hepatoma cells. J Canc Res Clin Oncol 131(6):385–394

    Article  CAS  Google Scholar 

  11. Weichert W (2009) HDAC expression and clinical prognosis in human malignancies. Canc Lett 280(2):168–176

    Article  CAS  Google Scholar 

  12. Fritzsche FR, Weichert W, Roske A, Gekeler V, Beckers T, Stephan C, Jung K, Scholman K, Denkert C, Dietel M, Kristiansen G (2008) Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer. BMC Canc 8:381

    Article  Google Scholar 

  13. Ouaissi M, Sielezneff I, Silvestre R, Sastre B, Bernard JP, Lafontaine JS, Payan MJ, Dahan L, Pirro N, Seitz JF, Mas E, Lombardo D, Ouaissi A (2008) High histone deacetylase 7 (HDAC7) expression is significantly associated with adenocarcinomas of the pancreas. Ann Surg Oncol 15(8):2318–2328

    Article  PubMed  Google Scholar 

  14. Weichert W, Roske A, Gekeler V, Beckers T, Ebert MP, Pross M, Dietel M, Denkert C, Rocken C (2008) Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis. Lancet Oncol 9(2):139–148

    Article  PubMed  CAS  Google Scholar 

  15. Weichert W, Roske A, Niesporek S, Noske A, Buckendahl AC, Dietel M, Gekeler V, Boehm M, Beckers T, Denkert C (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 Canc Res 14(6):1669–1677

    Article  CAS  Google Scholar 

  16. Rikimaru T, Taketomi A, Yamashita Y, Shirabe K, Hamatsu T, Shimada M, Maehara Y (2007) Clinical significance of histone deacetylase 1 expression in patients with hepatocellular carcinoma. Oncology 72(1–2):69–74

    Article  PubMed  CAS  Google Scholar 

  17. Lesko LJ, Atkinson AJ Jr (2001) Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies. Annu Rev Pharmacol Toxicol 41:347–366

    Article  PubMed  CAS  Google Scholar 

  18. Bakhtiar R (2008) Biomarkers in drug discovery and development. J Pharmacol Toxicol Meth 57(2):85–91

    Article  CAS  Google Scholar 

  19. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ (2008) Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Canc Inst 100(10):698–711

    Article  Google Scholar 

  20. Amann T, Maegdefrau U, Hartmann A, Agaimy A, Marienhagen J, Weiss TS, Stoeltzing O, Warnecke C, Scholmerich J, Oefner PJ, Kreutz M, Bosserhoff AK, Hellerbrand C (2009) GLUT1 expression is increased in hepatocellular carcinoma and promotes tumorigenesis. Am J Pathol 174(4):1544–1552

    Article  PubMed  CAS  Google Scholar 

  21. Hellerbrand C, Amann T, Schlegel J, Wild P, Bataille F, Spruss T, Hartmann A, Bosserhoff AK (2008) The novel gene MIA2 acts as a tumour suppressor in hepatocellular carcinoma. Gut 57(2):243–251

    Article  PubMed  CAS  Google Scholar 

  22. Tannapfel A, Denk H, Dienes HP, Langner C, Schirmacher P, Trauner M, Flott-Rahmel B (2010) Histopathological diagnose of non-alcoholic and alcoholic fatty liver disease. Z Gastroenterol 48(4):486–498

    Article  PubMed  CAS  Google Scholar 

  23. Sobin LH, Gospodarowicz MK, Wittekind C (2009) TNM Classification of Malignant Tumours. Wiley-Blackwell

  24. Weichert W, Denkert C, Noske A, Darb-Esfahani S, Dietel M, Kalloger SE, Huntsman DG, Kobel M (2008) Expression of class I histone deacetylases indicates poor prognosis in endometrioid subtypes of ovarian and endometrial carcinomas. Neoplasia 10(9):1021–1027

    PubMed  CAS  Google Scholar 

  25. Miyake K, Yoshizumi T, Imura S, Sugimoto K, Batmunkh E, Kanemura H, Morine Y, Shimada M (2008) Expression of hypoxia-inducible factor-1alpha, histone deacetylase 1, and metastasis-associated protein 1 in pancreatic carcinoma: correlation with poor prognosis with possible regulation. Pancreas 36(3):e1–e9

    Article  PubMed  CAS  Google Scholar 

  26. Lehmann A, Denkert C, Budczies J, Buckendahl AC, Darb-Esfahani S, Noske A, Muller BM, Bahra M, Neuhaus P, Dietel M, Kristiansen G, Weichert W (2009) High class I HDAC activity and expression are associated with RelA/p65 activation in pancreatic cancer in vitro and in vivo. BMC Canc 9:395

    Article  Google Scholar 

  27. Krusche CA, Wulfing P, Kersting C, Vloet A, Bocker W, Kiesel L, Beier HM, Alfer J (2005) Histone deacetylase-1 and −3 protein expression in human breast cancer: a tissue microarray analysis. Breast Canc Res Treat 90(1):15–23

    Article  CAS  Google Scholar 

  28. Glaser KB, Li J, Staver MJ, Wei RQ, Albert DH, Davidsen SK (2003) Role of class I and class II histone deacetylases in carcinoma cells using siRNA. Biochem Biophys Res Commun 310(2):529–536

    Article  PubMed  CAS  Google Scholar 

  29. Fakhry H, Miyamoto T, Kashima H, Suzuki A, Ke H, Konishi I, Shiozawa T (2010) Immunohistochemical detection of histone deacetylases in endometrial carcinoma: involvement of histone deacetylase 2 in the proliferation of endometrial carcinoma cells. Hum Pathol 41(6):848–858

    Article  PubMed  CAS  Google Scholar 

  30. Langer R, Mutze K, Becker K, Feith M, Ott K, Hofler H, Keller G (2010) Expression of class I histone deacetylases (HDAC1 and HDAC2) in oesophageal adenocarcinomas: an immunohistochemical study. J Clin Pathol 63:994–998

    Article  PubMed  CAS  Google Scholar 

  31. Hrzenjak A, Moinfar F, Kremser ML, Strohmeier B, Staber PB, Zatloukal K, Denk H (2006) Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells. Mol Canc Ther 5(9):2203–2210

    Article  CAS  Google Scholar 

  32. Huang BH, Laban M, Leung CH, Lee L, Lee CK, Salto-Tellez M, Raju GC, Hooi SC (2005) Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell Death Differ 12(4):395–404

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Peter Rexin and Susanne Lingelbach for their help in this study. This study is supported by a Research Grant of the University Medical Center Giessen and Marburg (UKGM).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Institute for Surgical Research, Philipps University Marburg, Baldingerstrasse, 35033, Marburg, Germany

    Karl Quint, Pietro Di Fazio, Roberta Montalbano, Helmut Sitter & Matthias Ocker

  2. Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany

    Karl Quint, Claudia Steindorf & Matthias Ocker

  3. Department of Pathology, University Hospital Erlangen, Erlangen, Germany

    Abbas Agaimy, Rudolf Jung & Arndt Hartmann

  4. Department of Pathology, University Hospital Regensburg, Regensburg, Germany

    Rudolf Jung

  5. Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany

    Claus Hellerbrand

  6. Institute of Pathology, Paracelsus Private Medical University, Salzburg, Austria

    Daniel Neureiter

Authors
  1. Karl Quint
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abbas Agaimy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pietro Di Fazio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roberta Montalbano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claudia Steindorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rudolf Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Claus Hellerbrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Arndt Hartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Helmut Sitter
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Daniel Neureiter
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Matthias Ocker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthias Ocker.

Electronic supplementary materials

Below is the link to the electronic supplementary material.

Online resource 1

HDAC expression stained on traditional slides. HDACs 1–3 are shown to be homogenously expressed in cancer cells throughout the tumor section. (PPT 429 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Quint, K., Agaimy, A., Di Fazio, P. et al. Clinical significance of histone deacetylases 1, 2, 3, and 7: HDAC2 is an independent predictor of survival in HCC. Virchows Arch 459, 129–139 (2011). https://doi.org/10.1007/s00428-011-1103-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-011-1103-0

Keywords

Search

Navigation