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:

Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8

Abstract

Mutation of the p53 gene is the most common genetic alteration in human cancer and contributes to malignant process by enhancing transformed properties of cells and resistance to anticancer therapy. Mutant p53 is often highly expressed in tumor cells at least, in part, due to its increased half-life. However, whether mutant p53 expression is regulated by other mechanisms in tumors is unclear. Here we found that histone deacetylase (HDAC) inhibitors suppress both wild-type and mutant p53 transcription in time- and dose-dependent manners. Consistent with this, the levels of wild-type and mutant p53 proteins are decreased upon treatment with HDAC inhibitors. Importantly, we found that upon knockdown of each class I HDAC, only HDAC8 knockdown leads to decreased expression of wild-type and mutant p53 proteins and transcripts. Conversely, we found that ectopic expression of wild-type, but not mutant HDAC8, leads to increased transcription of p53. Furthermore, we found that knockdown of HDAC8 results in reduced expression of HoxA5 and consequently, attenuated ability of HoxA5 to activate p53 transcription, which can be rescued by ectopic expression of HoxA5. Because of the fact that HDAC8 is required for expression of both wild-type and mutant p53, we found that targeted disruption of HDAC8 expression remarkably triggers proliferative defect in cells with a mutant, but not wild-type, p53. Together, our data uncover a regulatory mechanism of mutant p53 transcription via HDAC8 and suggest that HDAC inhibitors and especially HDAC8-targeting agents might be explored as an adjuvant for tumors carrying a mutant p53.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

  1. Minucci S, Pelicci PG . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6: 38–51.

    Article  CAS  Google Scholar 

  2. Halkidou K, Gaughan L, Cook S, Leung HY, Neal DE, Robson CN . Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. Prostate 2004; 59: 177–189.

    Article  CAS  Google Scholar 

  3. Song J, Noh JH, Lee JH, Eun JW, Ahn YM, Kim SY et al. Increased expression of histone deacetylase 2 is found in human gastric cancer. APMIS 2005; 113: 264–268.

    Article  CAS  Google Scholar 

  4. Huang BH, Laban M, Leung CH, Lee L, Lee CK, Salto-Tellez M et al. Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell Death Differ 2005; 12: 395–404.

    Article  CAS  Google Scholar 

  5. Hrzenjak A, Moinfar F, Kremser ML, Strohmeier B, Staber PB, Zatloukal K et al. Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells. Mol Cancer Ther 2006; 5: 2203–2210.

    Article  CAS  Google Scholar 

  6. Yang WM, Yao YL, Sun JM, Davie JR, Seto E . Isolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene family. J Biol Chem 1997; 272: 28001–28007.

    Article  CAS  Google Scholar 

  7. Wilson AJ, Byun DS, Popova N, Murray LB, L’Italien K, Sowa Y et al. Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. J Biol Chem 2006; 281: 13548–13558.

    Article  CAS  Google Scholar 

  8. Duvic M, Vu J . Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. Expert Opin Investig Drugs 2007; 16: 1111–1120.

    Article  CAS  Google Scholar 

  9. Ramalingam SS, Parise RA, Ramanathan RK, Lagattuta TF, Musguire LA, Stoller RG et al. Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res 2007; 13: 3605–3610.

    Article  CAS  Google Scholar 

  10. Munster PN, Thurn KT, Thomas S, Raha P, Lacevic M, Miller A et al. A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br J Cancer 2011; 104: 1828–1835.

    Article  CAS  Google Scholar 

  11. Kirschbaum M, Frankel P, Popplewell L, Zain J, Delioukina M, Pullarkat V et al. Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol 2011; 29: 1198–1203.

    Article  CAS  Google Scholar 

  12. Somoza JR, Skene RJ, Katz BA, Mol C, Ho JD, Jennings AJ et al. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure 2004; 12: 1325–1334.

    Article  CAS  Google Scholar 

  13. Ayer DE . Histone deacetylases: transcriptional repression with SINers and NuRDs. Trends Cell Biol 1999; 9: 193–198.

    Article  CAS  Google Scholar 

  14. David G, Neptune MA, DePinho RA . SUMO-1 modification of histone deacetylase 1 (HDAC1) modulates its biological activities. J Biol Chem 2002; 277: 23658–23663.

    Article  CAS  Google Scholar 

  15. Tsai SC, Seto E . Regulation of histone deacetylase 2 by protein kinase CK2. J Biol Chem 2002; 277: 31826–31833.

    Article  CAS  Google Scholar 

  16. Sengupta N, Seto E . Regulation of histone deacetylase activities. J Cell Biochem 2004; 93: 57–67.

    Article  CAS  Google Scholar 

  17. Lee H, Rezai-Zadeh N, Seto E . Negative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A. Mol Cell Biol 2004; 24: 765–773.

    Article  CAS  Google Scholar 

  18. Hu E, Chen Z, Fredrickson T, Zhu Y, Kirkpatrick R, Zhang GF et al. Cloning and characterization of a novel human class I histone deacetylase that functions as a transcription repressor. J Biol Chem 2000; 275: 15254–15264.

    Article  CAS  Google Scholar 

  19. Oehme I, Deubzer HE, Wegener D, Pickert D, Linke JP, Hero B et al. Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res 2009; 15: 91–99.

    Article  CAS  Google Scholar 

  20. Krennhrubec K, Marshall BL, Hedglin M, Verdin E, Ulrich SM . Design and evaluation of ‘Linkerless’ hydroxamic acids as selective HDAC8 inhibitors. Bioorg Med Chem Lett 2007; 17: 2874–2878.

    Article  CAS  Google Scholar 

  21. Reisman D, Loging WT . Transcriptional regulation of the p53 tumor suppressor gene. Semin Cancer Biol 1998; 8: 317–324.

    Article  CAS  Google Scholar 

  22. Raman V, Martensen SA, Reisman D, Evron E, Odenwald WF, Jaffee E et al. Compromised HOXA5 function can limit p53 expression in human breast tumours. Nature 2000; 405: 974–978.

    Article  CAS  Google Scholar 

  23. Wang S, El-Deiry WS . p73 or p53 directly regulates human p53 transcription to maintain cell cycle checkpoints. Cancer Res 2006; 66: 6982–6989.

    Article  CAS  Google Scholar 

  24. Terzian T, Suh YA, Iwakuma T, Post SM, Neumann M, Lang GA et al. The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes Dev 2008; 22: 1337–1344.

    Article  CAS  Google Scholar 

  25. Glozak MA, Sengupta N, Zhang X, Seto E . Acetylation and deacetylation of non-histone proteins. Gene 2005; 363: 15–23.

    Article  CAS  Google Scholar 

  26. Juan LJ, Shia WJ, Chen MH, Yang WM, Seto E, Lin YS et al. Histone deacetylases specifically down-regulate p53-dependent gene activation. J Biol Chem 2000; 275: 20436–20443.

    Article  CAS  Google Scholar 

  27. Luo J, Su F, Chen D, Shiloh A, Gu W . Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 2000; 408: 377–381.

    Article  CAS  Google Scholar 

  28. Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 2001; 107: 149–159.

    Article  CAS  Google Scholar 

  29. Harms KL, Chen X . Histone deacetylase 2 modulates p53 transcriptional activities through regulation of p53-DNA binding activity. Cancer Res 2007; 67: 3145–3152.

    Article  CAS  Google Scholar 

  30. Li D, Marchenko ND, Moll UM . SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis. Cell Death Differ 2011; 18: 1904–1913.

    Article  CAS  Google Scholar 

  31. Gui CY, Ngo L, Xu WS, Richon VM, Marks PA . Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci USA 2004; 101: 1241–1246.

    Article  CAS  Google Scholar 

  32. Witt O, Deubzer HE, Milde T, Oehme I . HDAC family: what are the cancer relevant targets? Cancer Lett 2009; 277: 8–21.

    Article  CAS  Google Scholar 

  33. Khan N, Jeffers M, Kumar S, Hackett C, Boldog F, Khramtsov N et al. Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem J 2008; 409: 581–589.

    Article  CAS  Google Scholar 

  34. Noureen N, Rashid H, Kalsoom S . Identification of type-specific anticancer histone deacetylase inhibitors: road to success. Cancer Chemother Pharmacol 2010; 66: 625–633.

    Article  CAS  Google Scholar 

  35. Davie JR . Inhibition of histone deacetylase activity by butyrate. J Nutr 2003; 133: 2485S–2493S.

    Article  CAS  Google Scholar 

  36. Kim HJ, Bae SC . Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res 2011; 3: 166–179.

    CAS  PubMed  Google Scholar 

  37. Dong G, Luo J, Kumar V, Dong Z . Inhibitors of histone deacetylases suppress cisplatin-induced p53 activation and apoptosis in renal tubular cells. Am J Physiol Renal Physiol 2010; 298: F293–F300.

    Article  CAS  Google Scholar 

  38. Dowling DP, Gantt SL, Gattis SG, Fierke CA, Christianson DW . Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors. Biochemistry 2008; 47: 13554–13563.

    Article  CAS  Google Scholar 

  39. Bertrand P . Inside HDAC with HDAC inhibitors. Eur J Med Chem 2010; 45: 2095–2116.

    Article  CAS  Google Scholar 

  40. Chen H, Rubin E, Zhang H, Chung S, Jie CC, Garrett E et al. Identification of transcriptional targets of HOXA5. J Biol Chem 2005; 280: 19373–19380.

    Article  CAS  Google Scholar 

  41. Yan W, Chen X . Identification of GRO1 as a critical determinant for mutant p53 gain of function. J Biol Chem 2009; 284: 12178–12187.

    Article  CAS  Google Scholar 

  42. Yan W, Chen X . Characterization of functional domains necessary for mutant p53 gain of function. J Biol Chem 2010; 285: 14229–14238.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  44. McCabe MT, Brandes JC, Vertino PM . Cancer DNA methylation: molecular mechanisms and clinical implications. Clin Cancer Res 2009; 15: 3927–3937.

    Article  CAS  Google Scholar 

  45. Chambers AE, Banerjee S, Chaplin T, Dunne J, Debernardi S, Joel SP et al. Histone acetylation-mediated regulation of genes in leukaemic cells. Eur J Cancer 2003; 39: 1165–1175.

    Article  CAS  Google Scholar 

  46. Glaser KB, Staver MJ, Waring JF, Stender J, Ulrich RG, Davidsen SK . Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther 2003; 2: 151–163.

    CAS  PubMed  Google Scholar 

  47. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Hideshima T et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA 2004; 101: 540–545.

    Article  CAS  Google Scholar 

  48. Peart MJ, Smyth GK, van Laar RK, Bowtell DD, Richon VM, Marks PA et al. Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci USA 2005; 102: 3697–3702.

    Article  CAS  Google Scholar 

  49. Sasakawa Y, Naoe Y, Sogo N, Inoue T, Sasakawa T, Matsuo M et al. Marker genes to predict sensitivity to FK228, a histone deacetylase inhibitor. Biochem Pharmacol 2005; 69: 603–616.

    Article  CAS  Google Scholar 

  50. Ruefli AA, Ausserlechner MJ, Bernhard D, Sutton VR, Tainton KM, Kofler R et al. The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species. Proc Natl Acad Sci USA 2001; 98: 10833–10838.

    Article  CAS  Google Scholar 

  51. Peart MJ, Tainton KM, Ruefli AA, Dear AE, Sedelies KA, O’Reilly LA et al. Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. Cancer Res 2003; 63: 4460–4471.

    CAS  PubMed  Google Scholar 

  52. Balasubramanian S, Ramos J, Luo W, Sirisawad M, Verner E, Buggy JJ . A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas. Leukemia 2008; 22: 1026–1034.

    Article  CAS  Google Scholar 

  53. Harms KL, Chen X . The C terminus of p53 family proteins is a cell fate determinant. Mol Cell Biol 2005; 25: 2014–2030.

    Article  CAS  Google Scholar 

  54. Liu G, Xia T, Chen X . The activation domains, the proline-rich domain, and the C-terminal basic domain in p53 are necessary for acetylation of histones on the proximal p21 promoter and interaction with p300/CREB-binding protein. J Biol Chem 2003; 278: 17557–17565.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work is supported in part by National Institutes of Health Grant R01 CA121137. We thank S Townson (Merck Pharmaceuticals) for SAHA.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to X Chen.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yan, W., Liu, S., Xu, E. et al. Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8. Oncogene 32, 599–609 (2013). https://doi.org/10.1038/onc.2012.81

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.81

Keywords

Search

Quick links