Skip to main content

Advertisement

SpringerLink
Log in

The Up-Regulation of Histone Deacetylase 8 Promotes Proliferation and Inhibits Apoptosis in Hepatocellular Carcinoma

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Histone deacetylase 8 (HDAC8), a member of class I HDACs, has been reported to be involved in transcriptional regulation, cell cycle progression, and developmental events, and several studies have shown that HDAC8 plays a critical role in tumorigenesis. However, the expression level and the potential role of HDAC8 in hepatocellular carcinoma (HCC) remain unclear.

Aim

The purpose of this study was to investigate protein expression of HDAC8 in HCC tissues and the effects of HDAC8 knockdown on the proliferation and apoptosis of liver cancer cells, and to explore the possible mechanisms.

Methods

First, we used quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemical staining, and western blot to examine the mRNA and protein expression of HDAC8 in HCC cell lines and tissues. Then, we assessed the correlation between clinicopathological parameters and the protein expression of HDAC8. Furthermore, we employed the interfering RNA method to explore the potential role of HDAC8 in HCC progression in vitro.

Results

Our results showed that expression of HDAC8 was significantly up-regulated both in HCC cell lines and tumor tissues compared to human normal liver cell line LO2 and corresponding non-tumor tissues. Moreover, we found that HDAC8 knockdown could dramatically inhibit HCC cell proliferation and enhance the apoptosis rate in vitro. Western blot revealed that intrinsic apoptotic pathway proteins, including BAX, BAD, and BAK, were elevated after HDAC8 knockdown. The cleavage of caspase-3 and PARP, which are downstream of intrinsic apoptotic pathway, were also enhanced. In addition, suppression of HDAC8 also elevated the expression of p53 and acetylation of p53 at Lys382, whereas the acetylation of p53 at Lys373 did not change.

Conclusions

Our study revealed that HDAC8 was overexpressed in HCC. HDAC8 knockdown suppresses tumor growth and enhances apoptosis in HCC via elevating the expression of p53 and acetylation of p53 at Lys382. HDAC8 might serve as a potential therapeutic target in HCC.

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
Fig. 4

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Wild CP, Hall AJ. Primary prevention of hepatocellular carcinoma in developing countries. Mutat Res. 2000;462:381–393.

    Article  PubMed  CAS  Google Scholar 

  3. Yoo HY, Patt CH, Geschwind JF, et al. The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time. J Clin Oncol. 2003;21:4329–4335.

    Article  PubMed  Google Scholar 

  4. Glozak MA, Seto E. Histone deacetylases and cancer. Oncogene. 2007;26:5420–5432.

    Article  PubMed  CAS  Google Scholar 

  5. Marks PA, Xu WS. Histone deacetylase inhibitors: potential in cancer therapy. J Cell Biochem. 2009;107:600–608.

    Article  PubMed  CAS  Google Scholar 

  6. 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;9:139–148.

    Article  PubMed  CAS  Google Scholar 

  7. 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;14:1669–1677.

    Article  PubMed  CAS  Google Scholar 

  8. Weichert W, Roske A, Gekeler V, et al. Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy. Br J Cancer. 2008;98:604–610.

    Article  PubMed  CAS  Google Scholar 

  9. Krusche CA, Wulfing P, Kersting C, et al. Histone deacetylase-1 and -3 protein expression in human breast cancer: a tissue microarray analysis. Breast Cancer Res Treat. 2005;90:15–23.

    Article  PubMed  CAS  Google Scholar 

  10. 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.

    Article  PubMed  Google Scholar 

  11. Weichert W, Denkert C, Noske A, et al. Expression of class I histone deacetylases indicates poor prognosis in endometrioid subtypes of ovarian and endometrial carcinomas. Neoplasia. 2008;10:1021–1027.

    PubMed  CAS  Google Scholar 

  12. Waltregny D, De Leval L, Glenisson W, et al. Expression of histone deacetylase 8, a class I histone deacetylase, is restricted to cells showing smooth muscle differentiation in normal human tissues. Am J Pathol. 2004;165:553–564.

    Article  PubMed  CAS  Google Scholar 

  13. Oehme I, Deubzer HE, Wegener D, et al. Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res. 2009;15:91–99.

    Article  PubMed  CAS  Google Scholar 

  14. Park SY, Jun JA, Jeong KJ, et al. Histone deacetylases 1, 6 and 8 are critical for invasion in breast cancer. Oncol Rep. 2011;25:1677–1681.

    PubMed  CAS  Google Scholar 

  15. Cheng J, Xie HY, Xu X, et al. NDRG1 as a biomarker for metastasis, recurrence and of poor prognosis in hepatocellular carcinoma. Cancer Lett. 2011;310:35–45.

    Article  PubMed  CAS  Google Scholar 

  16. Noske A, Denkert C, Schober H, et al. Loss of Gelsolin expression in human ovarian carcinomas. Eur J Cancer. 2005;41:461–469.

    Article  PubMed  CAS  Google Scholar 

  17. Zhang F, Wu LM, Zhou L, et al. Predictive value of expression and promoter hypermethylation of XAF1 in hepatitis B virus-associated hepatocellular carcinoma treated with transplantation. Ann Surg Oncol. 2008;15:3494–3502.

    Article  PubMed  Google Scholar 

  18. Martinou JC, Youle RJ. Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell. 2011;21:92–101.

    Article  PubMed  CAS  Google Scholar 

  19. Spierings D, McStay G, Saleh M, et al. Connected to death: the (unexpurgated) mitochondrial pathway of apoptosis. Science. 2005;310:66–67.

    Article  PubMed  CAS  Google Scholar 

  20. Datta SR, Katsov A, Hu L, et al. 14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation. Mol Cell. 2000;6:41–51.

    PubMed  CAS  Google Scholar 

  21. Nayak SK, Panesar PS, Kumar H. p53-Induced apoptosis and inhibitors of p53. Curr Med Chem. 2009;16:2627–2640.

    Article  PubMed  CAS  Google Scholar 

  22. Haupt S, Berger M, Goldberg Z, et al. Apoptosis: the p53 network. J Cell Sci. 2003;116:4077–4085.

    Article  PubMed  CAS  Google Scholar 

  23. Roy S, Packman K, Jeffrey R, et al. Histone deacetylase inhibitors differentially stabilize acetylated p53 and induce cell cycle arrest or apoptosis in prostate cancer cells. Cell Death Diff. 2005;12:482–491.

    Article  CAS  Google Scholar 

  24. Wu LM, Yang Z, Zhou L, et al. Identification of histone deacetylase 3 as a biomarker for tumor recurrence following liver transplantation in HBV-associated hepatocellular carcinoma. PLoS ONE. 2010;5:e14460.

    Article  PubMed  CAS  Google Scholar 

  25. Yang Z, Zhou L, Wu LM, et al. Combination of polymorphisms within the HDAC1 and HDAC3 gene predict tumor recurrence in hepatocellular carcinoma patients that have undergone transplant therapy. Clin Chem Lab Med. 2010;48:1785–1791.

    PubMed  CAS  Google Scholar 

  26. Debatin KM. Apoptosis pathways in cancer and cancer therapy. Cancer Immunol Immunother. 2004;53:153–159.

    Article  PubMed  Google Scholar 

  27. Leibowitz B, Yu J. Mitochondrial signaling in cell death via the Bcl-2 family. Cancer Biol Ther. 2010;9:417–422.

    Article  PubMed  CAS  Google Scholar 

  28. Amaral JD, Xavier JM, Steer CJ, et al. Targeting the p53 pathway of apoptosis. Curr Pharm Des. 2010;16:2493–2503.

    Article  PubMed  CAS  Google Scholar 

  29. Amaral JD, Xavier JM, Steer CJ, et al. The role of p53 in apoptosis. Discov Med. 2010;9:145–152.

    PubMed  Google Scholar 

  30. Fridman JS, Lowe SW. Control of apoptosis by p53. Oncogene. 2003;22:9030–9040.

    Article  PubMed  CAS  Google Scholar 

  31. Yan W, Liu S, Xu E, et al. Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8. Oncogene. 2013;32:599–609.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was sponsored by Grants from the National Natural Science Foundation of China (No. 81272281) and Zhejiang Provincial Natural Science Foundation for Young Distinguished Scholars (No. R2110125).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Hepatobiliary Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Jian Wu, Chengli Du, Zhen Lv, Chaofeng Ding, Jun Cheng, Haiyang Xie, Lin Zhou & Shusen Zheng

Authors
  1. Jian Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chengli Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhen Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chaofeng Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haiyang Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lin Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shusen Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shusen Zheng.

Additional information

Jian Wu and Chengli Du contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, J., Du, C., Lv, Z. et al. The Up-Regulation of Histone Deacetylase 8 Promotes Proliferation and Inhibits Apoptosis in Hepatocellular Carcinoma. Dig Dis Sci 58, 3545–3553 (2013). https://doi.org/10.1007/s10620-013-2867-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-013-2867-7

Keywords

Search

Navigation