Skip to main content

Advertisement

SpringerLink
Log in

Growth-suppressive effect of suberoylanilide hydroxamic acid (SAHA) on human oral cancer cells

  • Original Paper
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Purpose

The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) has been reported to exhibit anticancer activities in various cancer cell types, but as yet there are few reports on the anticancer effects of SAHA in oral squamous cell carcinoma (OSCC)-derived cells and xenograft models.

Methods

The anti-proliferative and apoptotic activities of SAHA were assessed in human HSC-3 and HSC-4 (OSCC)-derived cell lines and JB6 normal mouse skin-derived epidermal cells using histone acetylation, soft agar colony formation, trypan blue exclusion, 4′-6-diamidino-2-phenylindole (DAPI) staining, Live/Dead viability/cytotoxicity and Western blot analyses.

Results

We found that SAHA treatment resulted in hyperacetylation of histones H2A and H3 and a concomitant decrease in the viability of HSC-3 and HSC-4 cells. SAHA also significantly inhibited the neoplastic transformation of JB6 cells treated with TPA, whereas the viability of these cells was not affected by this treatment. Additionally, we found that SAHA suppressed the anchorage-independent growth (colony forming capacity in soft agar) of HSC-3 and HSC-4 cells. DAPI staining, Live/Dead and Western blot analyses revealed that SAHA can induce caspase-dependent apoptosis in HSC-3 and HSC-4 cells. We also found that SAHA treatment led to inhibition of ERK phosphorylation, and that two MEK inhibitors potentiated SAHA-mediated apoptosis. Okadaic acid treatment inhibited SAHA-mediated apoptosis in both the HSC-3 and HSC-4 cell lines, wheras SAHA induced a profound in vivo inhibition of tumor growth in HSC-3 xenografts.

Conclusions

Our results indicate that the ERK signaling pathway may constitute a critical denominator of SAHA-induced apoptosis in OSCC-derived cells and that SAHA may have therapeutic potential for OSCC.

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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. C. Florean, M. Schnekenburger, C. Grandjenette, M. Dicato, M. Diederich, Epigenomics of leukemia: from mechanisms to therapeutic applications. Epigenomics 3, 581–609 (2011). doi:10.2217/epi.11.73

    Article  CAS  PubMed  Google Scholar 

  2. P. Zhu, E. Martin, J. Mengwasser, P. Schlag, K.P. Janssen, M. Gottlicher, Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell 5, 455–463 (2004)

    Article  CAS  PubMed  Google Scholar 

  3. Z. Zhang, H. Yamashita, T. Toyama, H. Sugiura, Y. Ando, K. Mita, M. Hamaguchi, Y. Hara, S. Kobayashi, H. Iwase, Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast. Breast Cancer Res. Treat. 94, 11–16 (2005). doi:10.1007/s10549-005-6001-1

    Article  CAS  PubMed  Google Scholar 

  4. E. Yiannakopoulou, Targeting epigenetic mechanisms and microRNAs by aspirin and other non steroidal anti-inflammatory agents–implications for cancer treatment and chemoprevention. Cell. Oncol. 37, 167–178 (2014). doi:10.1007/s13402-014-0175-7

    Article  CAS  Google Scholar 

  5. B.H. Huang, M. Laban, C.H. Leung, L. Lee, C.K. Lee, M. Salto-Tellez, G.C. Raju, S.C. Hooi, Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell Death Differ. 12, 395–404 (2005). doi:10.1038/sj.cdd.4401567

    Article  CAS  PubMed  Google Scholar 

  6. K.B. Glaser, J. Li, M.J. Staver, R.Q. Wei, D.H. Albert, S.K. Davidsen, Role of class I and class II histone deacetylases in carcinoma cells using siRNA. Biochem. Biophys. Res. Comm. 310, 529–536 (2003)

    Article  CAS  PubMed  Google Scholar 

  7. P.A. Marks, The clinical development of histone deacetylase inhibitors as targeted anticancer drugs. Expert Opin. Investig. Drugs 19, 1049–1066 (2010). doi:10.1517/13543784.2010.510514

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. H. Yamamoto, J. Fujimoto, E. Okamoto, J. Furuyama, T. Tamaoki, T. Hashimoto-Tamaoki, Suppression of growth of hepatocellular carcinoma by sodium butyrate in vitro and in vivo. Int. J. Cancer 76, 897–902 (1998)

    Article  CAS  PubMed  Google Scholar 

  9. S.T. Nawrocki, J.S. Carew, L. Douglas, J.L. Cleveland, R. Humphreys, J.A. Houghton, Histone deacetylase inhibitors enhance lexatumumab-induced apoptosis via a p21Cip1-dependent decrease in survivin levels. Cancer Res. 67, 6987–6994 (2007). doi:10.1158/0008-5472.CAN-07-0812

    Article  CAS  PubMed  Google Scholar 

  10. D. Siegel, M. Hussein, C. Belani, F. Robert, E. Galanis, V.M. Richon, J. Garcia-Vargas, C. Sanz-Rodriguez, S. Rizvi, Vorinostat in solid and hematologic malignancies. J. Hematol. Oncol. 2, 31 (2009). doi:10.1186/1756-8722-2-31

    Article  PubMed Central  PubMed  Google Scholar 

  11. D. Kurundkar, R.K. Srivastava, S.C. Chaudhary, M.E. Ballestas, L. Kopelovich, C.A. Elmets, M. Athar, Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model. Toxicol. Appl. Pharmacol. 266, 233–244 (2013). doi:10.1016/j.taap.2012.11.002

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. G. Silva, B.A. Cardoso, H. Belo, A.M. Almeida, Vorinostat induces apoptosis and differentiation in myeloid malignancies: genetic and molecular mechanisms. PLoS One 8, e53766 (2013). doi:10.1371/journal.pone.0053766

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. M.N. Siddiquey, H. Nakagawa, S. Iwata, T. Kanazawa, M. Suzuki, K. Imadome, S. Fujiwara, F. Goshima, T. Murata, H. Kimura, Anti-tumor effects of suberoylanilide hydroxamic acid on Epstein-Barr virus-associated T cell and natural killer cell lymphoma. Cancer Sci. 105, 713–722 (2014). doi:10.1111/cas.12418

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. S. Chen, Y. Zhao, W.F. Gou, S. Zhao, Y. Takano, H.C. Zheng, The anti-tumor effects and molecular mechanisms of suberoylanilide hydroxamic acid (SAHA) on the aggressive phenotypes of ovarian carcinoma cells. PLoS One 8, e79781 (2013). doi:10.1371/journal.pone.0079781

    Article  PubMed Central  PubMed  Google Scholar 

  15. C. Cortes, S.C. Kozma, A. Tauler, S. Ambrosio, MYCN concurrence with SAHA-induced cell death in human neuroblastoma cells. Cell. Oncol. 38, 341–352 (2015). doi:10.1007/s13402-015-0233-9

    Article  CAS  Google Scholar 

  16. L. Ellis, R. Pili, Histone deacetylase inhibitors: advancing therapeutic strategies in hematological and solid malignancies. Pharmaceuticals 3, 2411–2469 (2010). doi:10.3390/ph3082441

    Article  PubMed  Google Scholar 

  17. D. Yin, J.M. Ong, J. Hu, J.C. Desmond, N. Kawamata, B.M. Konda, K.L. Black, H.P. Koeffler, Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor: effects on gene expression and growth of glioma cells in vitro and in vivo. Clin Cancer Res 13, 1045–1052 (2007). doi:10.1158/1078-0432.CCR-06-1261

    Article  CAS  PubMed  Google Scholar 

  18. P.N. Munster, T. Troso-Sandoval, N. Rosen, R. Rifkind, P.A. Marks, V.M. Richon, The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Res. 61, 8492–8497 (2001)

    CAS  PubMed  Google Scholar 

  19. J.A. Shin, G. Han, H.J. Kim, H.M. Kim, S.D. Cho, Chemopreventive and chemotherapeutic effect of a novel histone deacetylase inhibitor, by specificity protein 1 in MDA-MB-231 human breast cancer cells. Eur. J. Cancer Prev. 23, 277–285 (2014). doi:10.1097/CEJ.0000000000000041

    Article  PubMed  Google Scholar 

  20. A. Hrzenjak, F. Moinfar, M.L. Kremser, B. Strohmeier, E. Petru, K. Zatloukal, H. Denk, Histone deacetylase inhibitor vorinostat suppresses the growth of uterine sarcomas in vitro and in vivo. Mol. Cancer 9, 49 (2010). doi:10.1186/1476-4598-9-49

    Article  PubMed Central  PubMed  Google Scholar 

  21. X. Sun, Z.S. Hasanali, A. Chen, D. Zhang, X. Liu, H.G. Wang, D.J. Feith, T.P. Loughran Jr., K. Xu, Suberoylanilide hydroxamic acid (SAHA) and cladribine synergistically induce apoptosis in NK-LGL leukaemia. Br. J. Haematol. 168, 371–383 (2015). doi:10.1111/bjh.13143

    Article  CAS  PubMed  Google Scholar 

  22. Y. Wang, W.Z. Kong, L.H. Xing, X. Yang, Effects and mechanism of suberoylanilide hydroxamic acid on the proliferation and apoptosis of human hepatoma cell line bel-7402. J. BUON 19, 698–704 (2014)

    PubMed  Google Scholar 

  23. T.G. Lee, E.H. Jeong, S.Y. Kim, H.R. Kim and C.H. Kim, The combination of irreversible EGFR TKIs and SAHA induces apoptosis and autophagy-mediated cell death to overcome acquired resistance in EGFR T790M-mutated lung cancer. Int. J. Cancer (2014) doi:10.1002/ijc.29320

  24. R.T. Allen, W.J. Hunter 3rd, D.K. Agrawal, Morphological and biochemical characterization and analysis of apoptosis. J. Pharmacol. Toxicol. Methods 37, 215–228 (1997)

    Article  CAS  PubMed  Google Scholar 

  25. Z. Jin, W.S. El-Deiry, Overview of cell death signaling pathways. Cancer Biol. Ther. 4, 139–163 (2005)

    Article  CAS  PubMed  Google Scholar 

  26. M. Suzuki, M. Endo, F. Shinohara, S. Echigo, H. Rikiishi, Enhancement of cisplatin cytotoxicity by SAHA involves endoplasmic reticulum stress-mediated apoptosis in oral squamous cell carcinoma cells. Cancer Chemother. Pharmacol. 64, 1115–1122 (2009). doi:10.1007/s00280-009-0969-x

    Article  CAS  PubMed  Google Scholar 

  27. Y.H. Kim, D.H. Lee, J.H. Jeong, Z.S. Guo, Y.J. Lee, Quercetin augments TRAIL-induced apoptotic death: involvement of the ERK signal transduction pathway. Biochem. Pharmacol. 75, 1946–1958 (2008). doi:10.1016/j.bcp.2008.02.016

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. C.A. Hollmann, T. Owens, J. Nalbantoglu, T.J. Hudson, R. Sladek, Constitutive activation of extracellular signal-regulated kinase predisposes diffuse large B-cell lymphoma cell lines to CD40-mediated cell death. Cancer Res. 66, 3550–3557 (2006). doi:10.1158/0008-5472.CAN-05-2498

    Article  CAS  PubMed  Google Scholar 

  29. Y.J. Lee, H.N. Cho, J.W. Soh, G.J. Jhon, C.K. Cho, H.Y. Chung, S. Bae, S.J. Lee, Y.S. Lee, Oxidative stress-induced apoptosis is mediated by ERK1/2 phosphorylation. Exp. Cell Res. 291, 251–266 (2003)

    Article  CAS  PubMed  Google Scholar 

  30. F. Chang, L.S. Steelman, J.T. Lee, J.G. Shelton, P.M. Navolanic, W.L. Blalock, R.A. Franklin, J.A. McCubrey, Leukemia 17, 1263–1293 (2003). doi:10.1038/sj.leu.2402945

    Article  CAS  PubMed  Google Scholar 

  31. J.T. Lee Jr., J.A. McCubrey, Signal transduction mediated by the ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 16, 486–507 (2002). doi:10.1038/sj.leu.2402460

    Article  CAS  PubMed  Google Scholar 

  32. N.P. Judd, A.E. Winkler, O. Murillo-Sauca, J.J. Brotman, J.H. Law, J.S. Lewis Jr., G.P. Dunn, J.D. Bui, J.B. Sunwoo, R. Uppaluri, ERK1/2 regulation of CD44 modulates oral cancer aggressiveness. Cancer Res. 72, 365–374 (2012). doi:10.1158/0008-5472.CAN-11-1831

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Y. Wang, S.Y. Wang, C.M. Hou, Y.J. Xu, Z.Y. Du and X.D. Yu, J. Histone deacetylase inhibitor SAHA induces inactivation of MAPK signaling and apoptosis in HL-60 cells. J. Exp. Hematol./Chin. Ass. Pathophysiol. 15, 267–271 (2007)

  34. M.J. Nunes, M. Moutinho, I. Milagre, M.J. Gama and E. Rodrigues, J. Okadaic acid inhibits the trichostatin A-mediated increase of human CYP46A1 neuronal expression in a ERK1/2-Sp3-dependent pathway. Lipid Res. 53, 1910–1919 (2012) doi:10.1194/jlr.M027680

Download references

Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A1A2055874), the Ministry of Science ICT & Future Planning (2014R1A4A1005309) and research funds of the Chonbuk National University in 2015.

Author information

Authors and Affiliations

  1. Department of Oral Pathology, School of Dentistry, Institute of Oral Bioscience and Biodegradable Material, Chonbuk National University, Jeonju, 561-756, Republic of Korea

    Boonsil Jang, Ji-Ae Shin, Nam-Pyo Cho & Sung-Dae Cho

  2. Department of Oral and Maxillofacial Surgery, School of Dentistry, Chonbuk National University, Jeonju, 561-756, Republic of Korea

    Yong-Soo Kim

  3. Center of Animal Care and Use, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 406-840, Republic of Korea

    Ji-Young Kim

  4. Department of Oral Biochemistry, School of Dentistry, Institute of Oral Bioscience, Chonbuk National University, Jeonju, 561-756, Republic of Korea

    Ho-Keun Yi

  5. Division of Advanced Materials Engineering, Research Center for Advanced Materials Development and Institute of Biodegradable Materials, Chonbuk National University, Jeonju, 561-756, Republic of Korea

    Il-Song Park

Authors
  1. Boonsil Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ji-Ae Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong-Soo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ji-Young Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ho-Keun Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Il-Song Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nam-Pyo Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sung-Dae Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Nam-Pyo Cho or Sung-Dae Cho.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Boonsil Jang and Ji-Ae Shin equally contributed as first author.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jang, B., Shin, JA., Kim, YS. et al. Growth-suppressive effect of suberoylanilide hydroxamic acid (SAHA) on human oral cancer cells. Cell Oncol. 39, 79–87 (2016). https://doi.org/10.1007/s13402-015-0255-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-015-0255-3

Keywords

Search

Navigation