Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The histone deacetylase inhibitor trichostatin A induces GADD45γ expression via Oct and NF-Y binding sites

Oncogene volume 27, pages 1263–1272 (2008)Cite this article

Abstract

The GADD45γ protein is a potential tumor suppressor whose expression is reduced in several tumors. However, very little is known about the regulation of its expression. We have determined that the most relevant region of its promoter lies between nucleotides −112 and −54, relative to the transcription start site. Putative Oct and NF-Y elements were found in this region and factors belonging to these families interacted with these elements in vitro and with the promoter in vivo. Mutation of these elements reduced the basal activity of the promoter, suggesting that both sites are essential for basal expression. These factors interact with chromatin modifying proteins and we found that histone deacetylase 1 or silencing mediator for retinoid and thyroid hormone receptor overexpression reduced the basal activity of the promoter. In contrast, forced expression of the histone acetylase protein PCAF or cell treatment with the HDAC inhibitor trichostatin A increased GADD45γ mRNA levels and induced GADD45γ promoter activity through its Oct and NF-Y elements. Moreover, ectopic expression of a dominant-negative version of NF-YA strongly inhibited trichostatin A-induced activation of the promoter. Our data strongly suggest that inhibition of deacetylase activity could potentially be used for treatment of tumors where GADD45γ expression is reduced.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Balliet AG, Hollander MC, Fornace Jr AJ, Hoffman B, Liebermann DA . (2003). Comparative analysis of the genetic structure and chromosomal mapping of the murine GADD45g/CR6 gene. DNA Cell Biol 22: 457–468.

    Article  CAS  PubMed  Google Scholar 

  • Beadling C, Johnson KW, Smith KA . (1993). Isolation of interleukin 2-induced immediate-early genes. Proc Natl Acad Sci USA 90: 2719–2723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berger SL . (2002). Histone modifications in transcriptional regulation. Curr Opin Genet Dev 12: 142–148.

    Article  CAS  PubMed  Google Scholar 

  • Brockman JL, Schuler LA . (2005). Prolactin signals via Stat5 and Oct-1 to the proximal cyclin D1 promoter. Mol Cell Endocrinol 239: 45–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campanero MR, Armstrong M, Flemington E . (1999). Distinct cellular factors regulate the c-myb promoter through its E2F element. Mol Cell Biol 19: 8442–8450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campanero MR, Armstrong M, Flemington E . (2000). CpG methylation as a mechanism for the regulation of E2F activity. Proc Natl Acad Sci USA 97: 6481–6486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caretti G, Salsi V, Vecchi C, Imbriano C, Mantovani R . (2003). Dynamic recruitment of NF-Y and histone acetyltransferases on cell-cycle promoters. J Biol Chem 278: 30435–30440.

    Article  CAS  PubMed  Google Scholar 

  • Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A et al. (2005). MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 21: 2933–2942.

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Clark S, Birkeland M, Sung CM, Lago A, Liu R et al. (2002). Induction and superinduction of growth arrest and DNA damage gene 45 (GADD45) alpha and beta messenger RNAs by histone deacetylase inhibitors trichostatin A (TSA) and butyrate in SW620 human colon carcinoma cells. Cancer Lett 188: 127–140.

    Article  CAS  PubMed  Google Scholar 

  • Chung HK, Yi YW, Jung NC, Kim D, Suh JM, Kim H et al. (2003). GADD45gamma expression is reduced in anaplastic thyroid cancer and its reexpression results in apoptosis. J Clin Endocrinol Metab 88: 3913–3920.

    Article  CAS  PubMed  Google Scholar 

  • Constance CM, Morgan IV JI, Umek RM . (1996). C/EBPalpha regulation of the growth-arrest-associated gene GADD45. Mol Cell Biol 16: 3878–3883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Della Ragione F, Criniti V, Della Pietra V, Borriello A, Oliva A, Indaco S et al. (2001). Genes modulated by histone acetylation as new effectors of butyrate activity. FEBS Lett 499: 199–204.

    Article  CAS  PubMed  Google Scholar 

  • De Smaele E, Zazzeroni F, Papa S, Nguyen DU, Jin R, Jones J et al. (2001). Induction of GADD45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature 414: 308–313.

    Article  CAS  PubMed  Google Scholar 

  • Fan W, Richter G, Cereseto A, Beadling C, Smith KA . (1999). Cytokine response gene 6 induces p21 and regulates both cell growth and arrest. Oncogene 18: 6573–6582.

    Article  CAS  PubMed  Google Scholar 

  • Hinkley C, Perry M . (1992). Histone H2B gene-transcription during Xenopus early development requires functional co-operation between proteins bound to the CCAAT and octamer motifs. Mol Cell Biol 12: 4400–4411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirose T, Sowa Y, Takahashi S, Saito S, Yasuda C, Shindo N et al. (2003). p53-independent induction of GADD45 by histone deacetylase inhibitor: coordinate regulation by transcription factors Oct-1 and NF-Y. Oncogene 22: 7762–7773.

    Article  CAS  PubMed  Google Scholar 

  • Hollander MC, Sheikh MS, Bulavin DV, Lundgren K, Augeri-Henmueller L, Shehee R et al. (1999). Genomic instability in GADD45a-deficient mice. Nat Genet 23: 176–184.

    Article  CAS  PubMed  Google Scholar 

  • Huang W, Zhao S, Ammanamanchi S, Brattain M, Venkatasubbarao K, Freeman JW . (2005). Trichostatin A induces transforming growth factor beta type II receptor promoter activity and acetylation of Sp1 by recruitment of PCAF/p300 to a Sp1. NF-Y complex. J Biol Chem 280: 10047–10054.

    Article  CAS  PubMed  Google Scholar 

  • Inoue T, Kamiyama J, Sakai T . (1999). Sp1 and NF-Y synergistically mediate the effect of vitamin D(3) in the p27(Kip1)gene promoter that lacks vitamin D response elements. J Biol Chem 274: 32309–32317.

    Article  CAS  PubMed  Google Scholar 

  • Jiang F, Wang Z . (2004). GADD45γ is androgen-responsive and growth-inhibitory in prostate cancer cells. Mol Cell Endocrinol 213: 121–129.

    Article  CAS  PubMed  Google Scholar 

  • Jin S, Fan F, Fan W, Zhao H, Tong T, Blanck P et al. (2001). Transcription factors Oct-1 and NF-YA regulate the p53-independent induction of the GADD45 following DNA damage. Oncogene 20: 2683–2690.

    Article  CAS  PubMed  Google Scholar 

  • Jin S, Tong T, Fan W, Fan F, Antinore MJ, Zhu X et al. (2002). GADD45-induced cell cycle G2-M arrest associates with altered subcellular distribution of cyclin B1 and is independent of p38 kinase activity. Oncogene 21: 8696–8704.

    Article  CAS  PubMed  Google Scholar 

  • Johnstone RW . (2002). Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1: 287–299.

    Article  CAS  PubMed  Google Scholar 

  • Jung N, Yi YW, Kim D, Shong M, Hong SS, Lee HS et al. (2000). Regulation of GADD45γ expression by C/EBP. Eur J Biochem 267: 6180–6187.

    Article  CAS  PubMed  Google Scholar 

  • Kakizawa T, Miyamoto T, Ichikawa K, Takeda T, Suzuki S, Mori J et al. (2001). Silencing mediator for retinoid and thyroid hormone receptors interacts with octamer transcription factor-1 and acts as a transcriptional repressor. J Biol Chem 276: 9720–9725.

    Article  CAS  PubMed  Google Scholar 

  • Kojima S, Mayumi-Matsuda K, Suzuki H, Sakata T . (1999). Molecular cloning of rat GADD45gamma, gene induction and its role during neuronal cell death. FEBS Lett 446: 313–317.

    Article  CAS  PubMed  Google Scholar 

  • Liebermann DA, Hoffman B . (2003). Myeloid differentiation (MyD) primary response genes in hematopoiesis. Blood Cells Mol Dis 31: 213–228.

    Article  CAS  PubMed  Google Scholar 

  • Lu B, Ferrandino AF, Flavell RA . (2004). GADD45beta is important for perpetuating cognate and inflammatory signals in T cells. Nat Immunol 5: 38–44.

    Article  CAS  PubMed  Google Scholar 

  • Lu B, Yu H, Chow C, Li B, Zheng W, Davis RJ et al. (2001). GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells. Immunity 14: 583–590.

    Article  CAS  PubMed  Google Scholar 

  • Mantovani R . (1999). The molecular biology of the CCAAT-binding factor NF-Y. Gene 239: 15–27.

    Article  CAS  PubMed  Google Scholar 

  • Mantovani R, Li XY, Pessara U, Hooft van Huisjduijnen R, Benoist C, Mathis D . (1994). Dominant negative analogs of NF-YA. J Biol Chem 269: 20340–20346.

    Article  CAS  PubMed  Google Scholar 

  • Marhin WW, Chen S, Facchini LM, Fornace Jr AJ, Penn LZ . (1997). Myc represses the growth arrest gene GADD45. Oncogene 14: 2825–2834.

    Article  CAS  PubMed  Google Scholar 

  • Mariadason JM, Corner GA, Augenlicht LH . (2000). Genetic reprogramming in pathways of colonic cell maturation induced by short chain fatty acids: comparison with trichostatin A, sulindac, and curcumin and implications for chemoprevention of colon cancer. Cancer Res 60: 4561–4572.

    CAS  PubMed  Google Scholar 

  • Nagy L, Kao HY, Chakravarti D, Lin RJ, Hassig CA, Ayer DE et al. (1997). Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89: 373–380.

    Article  CAS  PubMed  Google Scholar 

  • Nakayama K, Hara T, Hibi M, Hirano T, Miyajima A . (1999). A novel oncostatin M-inducible gene OIG37 forms a gene family with MyD118 and GADD45 and negatively regulates cell growth. J Biol Chem 274: 24766–24772.

    Article  CAS  PubMed  Google Scholar 

  • Osborne A, Zhang H, Yang WM, Seto E, Blanck G . (2001). Histone deacetylase activity represses gamma interferon-inducible HLA-DR gene expression following the establishment of a DNase I-hypersensitive chromatin conformation. Mol Cell Biol 21: 6495–64506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park SH, Lee SR, Kim BC, Cho EA, Patel SP, Kang HB et al. (2002). Transcriptional regulation of the transforming growth factor beta type II receptor gene by histone acetyltransferase and deacetylase is mediated by NF-Y in human breast cancer cells. J Biol Chem 277: 5168–5174.

    Article  CAS  PubMed  Google Scholar 

  • Peng Y, Jahroudi N . (2003). The NFY transcription factor inhibits von Willebrand factor promoter activation in non-endothelial cells through recruitment of histone deacetylases. J Biol Chem 278: 8385–8394.

    Article  CAS  PubMed  Google Scholar 

  • Smith ML, Ford JM, Hollander MC, Bortnick RA, Amundson SA, Seo YR et al. (2000). p53-mediated DNA repair responses to UV radiation: studies of mouse cells lacking p53, p21, and/or GADD45 genes. Mol Cell Biol 20: 3705–3714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun L, Gong R, Wan B, Huang X, Wu C, Zhang X et al. (2003). GADD45gamma, down-regulated in 65% hepatocellular carcinoma (HCC) from 23 Chinese patients, inhibits cell growth and induces cell cycle G2/M arrest for hepatoma Hep-G2 cell lines. Mol Biol Rep 30: 249–253.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi S, Saito S, Ohtani N, Sakai T . (2001). Involvement of the Oct-1 regulatory element of the GADD45 promoter in the p53-independent response to ultraviolet irradiation. Cancer Res 61: 1187–1195.

    CAS  PubMed  Google Scholar 

  • Takekawa M, Saito H . (1998). A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 95: 521–530.

    Article  CAS  PubMed  Google Scholar 

  • Vairapandi M, Balliet AG, Hoffman B, Liebermann DA . (2002). GADD45β and GADD45γ are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress. J Cell Physiol 192: 327–338.

    Article  CAS  PubMed  Google Scholar 

  • Yang J, Zhu H, Murphy TL, Ouyang W, Murphy KM . (2001). IL-18-stimulated GADD45 beta required in cytokine-induced, but not TCR-induced, IFN-gamma production. Nat Immunol 2: 157–164.

    Article  CAS  PubMed  Google Scholar 

  • Ying J, Srivastava G, Hsieh WS, Gao Z, Murray P, Liao SK et al. (2005). The stress-responsive gene GADD45γ is a functional tumor suppressor, with its response to environmental stresses frequently disrupted epigenetically in multiple tumors. Clin Cancer Res 11: 6442–6449.

    Article  CAS  PubMed  Google Scholar 

  • Yokota T, Matsuzaki Y, Miyazawa K, Zindy F, Roussel MF, Sakai T . (2004). Histone deacetylase inhibitors activate INK4d gene through Sp1 site in its promoter. Oncogene 23: 5340–5349.

    Article  CAS  PubMed  Google Scholar 

  • Zhan Q, Bae I, Kastan MB, Fornace Jr AJ . (1994). The p53-dependent gamma-ray response of GADD45. Cancer Res 54: 2755–2760.

    CAS  PubMed  Google Scholar 

  • Zhang W, Bae I, Krishnaraju K, Azam N, Fan W, Smith K et al. (1999). CR6: A third member in the MyD118 and GADD45 gene family which functions in negative growth control. Oncogene 18: 4899–48907.

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Hoffman B, Liebermann DA . (2001). Ectopic expression of MyD118/GADD45/CR6 (GADD45beta/alpha/gamma) sensitizes neoplastic cells to genotoxic stress-induced apoptosis. Int J Oncol 18: 749–757.

    PubMed  Google Scholar 

  • Zhang X, Sun H, Danila DC, Johnson SR, Zhou Y, Swearingen B et al. (2002). Loss of expression of GADD45 gamma, a growth inhibitory gene, in human pituitary adenomas: implications for tumorigenesis. J Clin Endocrinol Metab 87: 1262–12627.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr RM Evans, Dr T Kouzarides, Dr R Mantovani and Dr W Herr for providing plasmids. We thank Dr AC Carrera for helpful suggestions and M de la Fuente for excellent technical assistance. This work was supported by the Spanish Instituto de Salud Carlos III RTICCC (FIS03 C03/10) to VC and Spanish Ministerio de Educacion y Ciencia (SAF04-05888) and Spanish Instituto de Salud Carlos III (C03/10 and G03/179) to MRC.

Author information

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier, Madrid, Spain

    M R Campanero

  2. Departamento de Bioquímica e Instituto de Investigaciones Biomédicas Alberto Sols, UAM-CSIC, Facultad de Medicina de la Universidad Autónoma de Madrid-UAM, Madrid, Spain

    A Herrero & V Calvo

Authors
  1. M R Campanero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Herrero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V Calvo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V Calvo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Campanero, M., Herrero, A. & Calvo, V. The histone deacetylase inhibitor trichostatin A induces GADD45γ expression via Oct and NF-Y binding sites. Oncogene 27, 1263–1272 (2008). https://doi.org/10.1038/sj.onc.1210735

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210735

Keywords

This article is cited by

Search

Advanced search

Quick links