Skip to main content
SpringerLink
Log in

Effect of histone deacetylase inhibitor sodium butyrate (NaB) on transformants E1a+cHa-Ras expressing wild type p53 with suppressed transactivation function

  • Published:
Cell and Tissue Biology Aims and scope Submit manuscript

Abstract

The induction of cellular senescence by various antitumor agents is a promising strategy of cancer treatment. We assessed the ability of sodium butyrate (NaB), a histone deacetylase inhibitor (HDAC), to reactivate the cellular senescence program in the E1A+cHa-Ras-transformed rat embryo fibroblasts with wild-type p53 (ERasWT) and in the isogenic cell line, where p53 is inactivated due to expression of the active genetic suppressor element GSE56 (ERasGSE56). The NaB treatment increased the p53 transcriptional activity and induced an irreversible G1/S cell-cycle arrest in ERasWT, but not in ERasGSE56 cells. It was shown that, as a mark of p53 transactivation function, p53-LUC activity did not increase after the x-ray exposure of transformants ERasGSE56 by the transient transfection method using reporter p53 luciferase (p53-LUC) constructions. In transformants ERasWT, the p53 activity increased both after irradiation and upon NaB treatment. Interestingly, the expression of senescence-associated β-galactosidase (SA-β-Gal) widely used as a marker of senescence, as well as the loss of clonogenic ability were observed in both cell lines after NaB treatment. However, the expression of the SA-β-Gal and the inhibition of the capability for cloning are observed regardless of block on the G1-S cell cycle phase boundary in transformants of the both cell line. Thus, our obtained data suggest that induction of p53 transcriptional activity could be the key determinant of the HDACi-induced cell-cycle arrest and senescence in transformed cells and provide an additional evidence for the SA-β-Gal invalidity as a sufficient senescence marker.

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

Similar content being viewed by others

Abbreviations

b.p.:

the base pair

HDAC:

histone deacetylases

NaB:

sodium butyrate

PBS:

phosphatebuffer saline

SA-β-Gal:

senescence-associated-β-galactosidase

References

  • Abramova, M.V., Pospelova, T.V., Nikulenkov, F.P., Hollander, C.M., Fornace, A.J., Jr., and Pospelov, V.A., G1/S Arrest Induced by Histone Deacetylase Inhibitor Sodium Buturate in E1A + Ras-Transformed Cells Is Mediated through Down-Regulation of E2F Activity and Stabilization of β-Catenin, J. Biol. Chem., 2006, vol. 281, pp. 21040–21051.

    Article  CAS  PubMed  Google Scholar 

  • Aliouat-Denis, C.M., Dendouga, N., Vanden Wyngaert, I., Goehlmann, H., Steller, U., va de Weyer, I., Van Slycken, N., Andries, L., Kass, S., Luyten, W., Janicot, M., and Vialard, J.E., P53-Independent Regulation of p21Wafl/Cip1 Expression and Senescence by Chk2, Mol. Cancer Res., 2005, vol. 3, pp. 627–634.

    Article  CAS  PubMed  Google Scholar 

  • Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., Vassiliou, L.V., Kolettas, E., Niforou, K., and Zoumpourlis, V.C., Oncogene-Induced Senescence Is Part of the Tumorigenesis Barrier Imposed by DNA Damage Checkpoints, Nature, 2006, vol. 444, pp. 633–637.

    Article  CAS  PubMed  Google Scholar 

  • Beauséjour, C.M., Krtolica, A., Galimi, F., Narita, M., Lowe, S.W., Yaswen, P., and Campisi, J., Reversal of Human Cellular Senescence: Roles of the p53 and P16 Pathways, EMBO J., 2003, vol. 22, pp. 4212–4222.

    Article  PubMed  Google Scholar 

  • Blumenthal, R.D., An Overiew of Chemosensitivity Testing, Meth. Mol. Med., 2005, vol. 110, pp. 3–18.

    CAS  Google Scholar 

  • Braithwaite, A.W., Del Sal, G., and Lu, X., Some p53-Binding Proteins that Can Function as Arbiters of Life and Death, Cell Death Diff., 2006, vol. 13, pp. 984–993.

    Article  CAS  Google Scholar 

  • Bulavin, D.V., Tararova, N.D., Aksenov, N.D., Pospelov, V.A., and Pospelova, T.V., Deregulation of P53/P21/Cip1/Waf1 Pathway Contributes to Polyploidy and Apoptosis of E1A + CHa-Ras Transformed Cells After γ-Irradiation, Oncogene, 1999, vol. 18, pp. 5611–5619.

    Article  CAS  PubMed  Google Scholar 

  • Callodo, M. and Serrano, M., The Senescent Side of Tumor Suppression, Cell Cycle, 2005, vol. 4, pp. 1722–1724.

    Google Scholar 

  • Caron, C., Boyault, C., and Khochbin, S., Regulatory Cross-Talk between Lysine Acetylation and Ubiquitinilation: Role in the Control of Protein Stability, Bioassay, 2005, vol. 27, pp. 408–415.

    Article  CAS  Google Scholar 

  • Carlisis, D., Vassalo, B., Lauricella, M., Emanuele, S., DAnneo, A., Di Leonardo, E., Di Fazio, P., Vento, R., and Tesoriere, G., Histone Deacetylase Inhibitors Induce in Human Hepatoma HepG2 Cells Acetylation of p53 and Histones in Correlation with Apoptotic Effects, Int. J. Oncol., 2008, vol. 32, pp. 177–184.

    Google Scholar 

  • Chang, B.D., Watanabe, K., Broude, E.V., Fang, J., Poole, J.C., Kalinichenko, T.V., and Roninson, I.B., Effects of p21Waf1/Cip1/Sdi1 on Cellular Gene Expression: Implications for Carcinogenesis, Senescence, and Age-Related Diseases, Proc. Natl. Acad. Sci. USA., 200, vol. 97, pp. 4291–4296.

  • Chen, X., Ko, L.J., Jayaraman, L., and Prives, C., P53 Levels, Functional Domains, and DNA Damage Determine the Extent of the Apoptotic Response of Tumor Cells, Genes Dev., 1996, vol. 10, pp. 2438–2451.

    Article  CAS  PubMed  Google Scholar 

  • Coles, A.H., Liang, H., Zhu, Z., Marfella, C.G., Kang, J., Imbalzano, A.N., and Jones, S.N., Deletion of p37ln1 in Mice Reveals a p53-Independent Role for Ing1 in the Suppression of Cell Proliferation, Apoptosis, and Tumorigenesis. Cancer Res., 2007, vol. 67, pp. 2054–2061.

    Article  CAS  PubMed  Google Scholar 

  • Collado, M. and Serrano, M., The Power and the Promise of Oncogene-Induced Senescence Markers, Nat. Rev. Cancer., 2006, vol. 6, pp. 472–476.

    Article  CAS  PubMed  Google Scholar 

  • Collado, M., Blasco, M.A., and Serrano, M., Cellular Senescence in Cancer and Aging, Cell, 2007, vol. 130, pp. 223–233.

    Article  CAS  PubMed  Google Scholar 

  • Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A.J., Barradas, M., Benguria, A., Zaballos, A., Flores, J.M., Barbacid, M., Beach, D., and Serrano, M., Tumour Biology: Senescence in Premalignant Tumours, Nature, 2005, vol. 436, pp. 642.

    Article  CAS  PubMed  Google Scholar 

  • Condorelli, F., Gnemmi, I., Vallario, A., Genazzani, A.A., and Canonico, P.L., Inhibitors of Histone Deacetylase (HDAC) Resore the p53 Pathway in Neuroblastoma Cells, Br. J. Pharmacology, 2008, vol. 153, pp. 657–668.

    Article  CAS  Google Scholar 

  • Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., Schurra, C., Garre, M., Naciforo, P.G., and Bensimon, A., Oncogene-Induced Senescence Is a DNA Damage Response Triggered by DNA Hyper-Replication, Nature, 2006, vol. 444, pp. 638–642.

    Article  PubMed  Google Scholar 

  • Dimri, G.P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E.E., Linskens, M., Rubelj, I., Pereira-Smith O., Peacocke, M., and Campisi, J., A Biomarker that Identifies Senescent Human Cells in Culture and in Aging Skin in Vivo, Proc. Natl. Acad. Sci. USA, 1995, vol. 92, pp. 9363–9367.

    Article  CAS  PubMed  Google Scholar 

  • Gronroos, E., Hellman, U., Heldin, C.H., Erisson, J., Control of Smad7 Stability by Competition between Acetylation and Ubiquitinilation, Mol. Cell., 2002, vol. 10, pp. 438–493.

    Article  Google Scholar 

  • Ha, L., Ichikawa, T., Anver, M., Dickins, R., Lowe, S., Sharpless, N.E., Krimpenfort, P., Depinho, R.A., Bennett, D.C., Sviderskaya, E.V., and Merlino, G., ARF Functions as a Melanoma Tumor Suppressor by Inducing p53-Independent Senescence, Proc. Natl. Acad. Sci. USA., 2007, vol. 104, pp. 10968–10973.

    Article  CAS  PubMed  Google Scholar 

  • Hamroun, D., Kato, S., Ishioka, C., Claustres, M., Beround, C., and Soussi, T., The UMD TP53 Database and Website: Update and Revisions, Hum. Mutat., 2006, vol. 27, pp. 14–20.

    Article  CAS  PubMed  Google Scholar 

  • Harms, K., Nozell, S.,and Chen, X., The Common and Distinct Target Genes of the p53 Family Transcription Factors, Cell. Mol. Life Sci., 2004, vol. 61, pp. 822–842.

    Article  CAS  PubMed  Google Scholar 

  • Johnstone, R.W. and Licht, J.D., Histone Deacetylase Inhibitors in Cancer Therapy: Is Transcription the Primary Target, Cancer Cell., 2003, vol. 4, pp. 13–18.

    Article  CAS  PubMed  Google Scholar 

  • Lee, B.Y., Han, J.A., Im, J.S., Morrone, A., Johung, K., Goodwin, E.C., Kleijer, W.J., DiMaio, D., and Hwang, E.S., Senescence-Associated Beta-Galactosidase Is Lysosomal Beta-Galactosidase, Aging Cell, 2006, vol. 5, pp. 187–195.

    Article  CAS  PubMed  Google Scholar 

  • Lindemann, R.K., Gabrielli, B., and Johnstone, R.W, Histone-Deacetylase Inhibitors for the Treatment of Cancer, Cell Cycle, 2004, vol. 3, pp. 779–788.

    CAS  PubMed  Google Scholar 

  • Luong, Q.T., OKelly, J., Braunstein, G.D., Hershman, J.M., and Koeffler, H.P., Antitumor Activity of Syberoylanilide Hydroxamic Acid Against Thyroid Cancer Cell Lines in Vitro and in Vivo, Clin. Cancer Res., 2006, vol. 12, pp. 55700–5577.

    Article  Google Scholar 

  • Marks, P.A. and Breslov, R., Dimethyl Sulfoxide to Vorinostat: Development of this Histone Deacetylase Inhibitor as an Anticancer Drug, Nat. Biotechnol., 2007, vol. 25, pp. 84–90.

    Article  CAS  PubMed  Google Scholar 

  • Martins, C.P., Brown-Swigart, L., and Evan, C.I., Modeling the Therapeutic Efficacy of p53 Restoration in Tumors, Cell, 2006, vol. 127, pp. 1323–1334.

    Article  CAS  PubMed  Google Scholar 

  • Ossovskaya, V.S., Mazo I.A., Chernov, M.V., Chernova, O.B., Strezoska, Z., Kondratov, R., Stark, G.R., Chumakov, P.M., and Gudkov, A.V., Use of Genetic Suppressor Elements to Dissect Distinct Biological Effects of Separate p53 Domains, Proc. Natl. Acad. Sci. USA., 1996, vol. 93, pp. 10309–10314.

    Article  CAS  PubMed  Google Scholar 

  • Parrinello, S., Samper, E., Krtolica, A., Goldstein, J., Melov, S., and Campisi, J., Oxygen Sensitivity Severely Limits the Replicative Lifespan of Murine Fibroblasts, Nat. Cell Biol., 2003, vol. 5, pp. 741–747.

    Article  CAS  PubMed  Google Scholar 

  • Petitjean, A., Mathe, E., Kato, S., Ishioka, C., Tavtigian, S.V, Hainaut, P., and Olivier, M., Impact of Mutant p53 Functional Properties on TP53 Mutation Patterns and Tumor Phenotype: Lessons from Recent Developments in the IARC TP53 Database, Hum. Mutat., 2007, vol. 28, pp. 622–629.

    Article  CAS  PubMed  Google Scholar 

  • Richon, V.M., Sandhoff, T.W., Rifkind, R.A., and Marks, P.A., Histone Deacetylase Inhibitor Selectively Induces p21Waf1 Expression and Gene-Associated Histone Acetylation, Proc. Natl. Acad. Sci. USA, 2000, vol. 97, pp. 10014–10019.

    Article  CAS  PubMed  Google Scholar 

  • Roberson, R.S., Kussick, S.J., Vallieres, E., Chen, S.Y., and Wu, D.Y., Escape from Therapy-Induced Accelerated Cellular Senescence in p53-Null Lung Cancer Cells and in Human Lung Cancers, Cancer Res., 2005, vol. 65, pp. 2795–2803.

    Article  CAS  PubMed  Google Scholar 

  • Rodier, F., Campisi, J., and Bhaumik, D., Two Faces of p53: Aging and Tumor Suppression, Nucleic Acids Res., 2007, vol. 35, pp. 7475–7484.

    Article  CAS  PubMed  Google Scholar 

  • Serrano, M., Lin, A.W., McCurrach, M.E., Beach, D., and Lowe, S.W., Oncogenic Ras Provokes Premature Cell Senescence Associates with Accumulation of p53 and p16INK4a, Cell, 1997, vol. 88, pp. 593–602.

    Article  CAS  PubMed  Google Scholar 

  • Sherr, C.J., The INK4a/ARF Network in Timour Suppression, Nat. Rev. Mol. Cell Biol., 2001, vol. 2, pp. 731–737.

    Article  CAS  PubMed  Google Scholar 

  • Te Poele, R.H., Okorokov, A.L., Jardine, L., Cummings, J., and Joel, S.P., DNA Damage is Able to Induce Senescence in Tumor Cells in Vitro and in Vivo, Cancer Res., 2002, vol. 62, pp. 1876–1883.

    Google Scholar 

  • Toledo, F. and Wahl, G.M., Regulating the p53 Pathway: In Vitro Hypotheses, in Vivo Veritas, Nat. Rev. Cancer., 2006, vol. 6, pp. 909–923.

    Article  CAS  PubMed  Google Scholar 

  • Ventura, A., Kirsch, D.G, McLaughlin, M.E, Tuveson, D.A, Grimm, J., Lintault, L., Newman, J., Reczek, E.E, Weissleder, R., and Jacks, T., Restoration of p53 Function Leads to Tumour Regression in Vivo, Nature, 2007, vol. 445, pp. 661–665.

    Article  CAS  PubMed  Google Scholar 

  • Xu, W.S., Parmigiani, R.B., and Marks, P.A., Histone Deacetylase Inhibitors: Molecular Mechanisms of Action, Oncogene, 2007, vol. 26, pp. 5541–5552.

    Article  CAS  PubMed  Google Scholar 

  • Xue, W., Zender, L., Miething, C., Dickins, R.A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., and Lowe, S.W., Senescence and Tumour Clearance is Triggered by p53 Restoration in Murine Liver Carcinomas, Nature, 2007, vol. 445, pp. 656–660.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, H., Molecular Signaling and Genetic Pathways of Senescence: Its Role in Tumorigenesis and Aging, Journal of Cellular Physiology, 2007, vol. 210, pp. 567–574.

    Article  CAS  PubMed  Google Scholar 

  • Zhou, J., Ahn, J., Wilson, S.H., and Prives, C., A Role for p53 in Base Excision Repair, EMBO J., 2001, vol. 20, pp. 914–923.

    Article  CAS  PubMed  Google Scholar 

  • Zubova, Yu.G., Bykova, T.V., Zubova, S.G., Abramova, M.V., Aksenov, N.D., Pospelov, V.A., and Pospelova, T.V., Induction of Premature Senescence Program by an Inhibitor of Histone Deacetylase Sodium Butyrate in Normal and Transformed Rat Fibroblasts, Tsitologiia, 2005, vol. 47, no. 12, pp. 1055–1062.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia

    E. I. Bukreeva, N. D. Aksenov, A. A. Bardin, V. A. Pospelov & T. V. Pospelova

Authors
  1. E. I. Bukreeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. D. Aksenov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. A. Bardin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V. A. Pospelov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. V. Pospelova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. I. Bukreeva.

Additional information

Original Russian Text © E.I. Bukreeva, N.D. Aksenov, A.A. Bardin, V.A. Pospelov, T.V. Pospelova, 2009, published in Tsitologiya, Vol. 51, No. 8, 2009, pp. 697–705.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bukreeva, E.I., Aksenov, N.D., Bardin, A.A. et al. Effect of histone deacetylase inhibitor sodium butyrate (NaB) on transformants E1a+cHa-Ras expressing wild type p53 with suppressed transactivation function. Cell Tiss. Biol. 3, 445–453 (2009). https://doi.org/10.1134/S1990519X09050071

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1990519X09050071

Key words

Search

Navigation