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 Paper
  • Published:

Activated p53 suppresses the histone methyltransferase EZH2 gene

Abstract

Replicative senescence is an irreversible cell cycle arrest that limits the proliferation of damaged cells and may be an important tumor suppression mechanism in vivo. This process is regulated at critical steps by the tumor suppressor p53. To identify genes that may regulate the senescence process, we performed cDNA microarray analysis of gene expression in senescent, young proliferating, and hTERT-immortalized primary human fibroblasts. The histone methyltransferase (HMTase), EZH2, was specifically downregulated in senescent cells. Activated p53 suppressed EZH2 gene expression through repression of the EZH2 gene promoter. This activity of p53 requires intact p53 transactivation and DNA binding domains. Furthermore, the repression of EZH2 promoter by p53 is dependent on p53 transcriptional target p21Waf1 inactivating RB/E2F pathways. In addition, the knockdown of EZH2 expression retards cell proliferation and induces G2/M arrest. We suggest that the p53-dependent suppression of EZH2 expression is a novel pathway that contributes to p53-mediated G2/M arrest. EZH2 associated complex possesses HMTase activity and is involved in epigenetic regulation. Activated p53 suppresses EZH2 expression, suggesting a further role for p53 in epigenetic regulation and in the maintenance of genetic stability. Suppression of EZH2 expression in tumors by p53 may lead to novel approaches to control cancer progression.

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

Similar content being viewed by others

References

  • Afshari CA, Vojta PJ, Annab LA, Futreal PA, Willard TB and Barrett JC . (1993). Exp. Cell Res., 209, 231–237.

  • Almog N and Rotter V . (1997). Biochim. Biophys. Acta, 1333, F1–F27.

  • Atadja P, Wong H, Garkavtsev I, Veillette C and Riabowol K . (1995). Proc. Natl. Acad. Sci. USA, 92, 8348–8352.

  • Blackburn EH . (2001). Cell, 106, 661–673.

  • Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S and Wright WE . (1998). Science, 279, 349–352.

  • Bond JA, Wyllie FS and Wynford-Thomas D . (1994). Oncogene, 9, 1885–1889.

  • Bracken AP, Pasini D, Capra M, Prosperini E, Colli E and Helin K . (2003). EMBO J., 22, 5323–5335.

  • Bringold F and Serrano M . (2000). Exp. Gerontol., 35, 317–329.

  • Brummelkamp TR, Bernards R and Agami R . (2002a). Cancer Cell, 2, 243–247.

  • Brummelkamp TR, Bernards R and Agami R . (2002b). Science, 296, 550–553.

  • Campisi J . (1996). Cell, 84, 497–500.

  • Campisi J . (2001). Trends Cell. Biol., 11, S27–S31.

  • Campisi J . (2003). Nat. Rev. Cancer, 3, 339–349.

  • Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS and Zhang Y . (2002). Science, 298, 1039–1043.

  • Czermin B, Melfi R, McCabe D, Seitz V, Imhof A and Pirrotta V . (2002). Cell, 111, 185–196.

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M and Campisi J . (1995). Proc. Natl. Acad. Sci. USA, 92, 9363–9367.

  • el-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW and Vogelstein B . (1992). Nat. Genet., 1, 45–49.

  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B . (1993). Cell, 75, 817–825.

  • Francis NJ and Kingston RE . (2001). Nat. Rev. Mol. Cell. Biol., 2, 409–421.

  • Fukuyama T, Otsuka T, Shigematsu H, Uchida N, Arima F, Ohno Y, Iwasaki H, Fukuda T and Niho Y . (2000). Br. J. Haematol., 108, 842–847.

  • Giaccia AJ and Kastan MB . (1998). Genes Dev., 12, 2973–2983.

  • Greider CW and Blackburn EH . (1987). Cell, 51, 887–898.

  • Hara E, Tsurui H, Shinozaki A, Nakada S and Oda K . (1991). Biochem. Biophys. Res. Commun., 179, 528–534.

  • Hayflick L . (1965). Exp. Cell Res., 37, 614–636.

  • Hermeking H, Lengauer C, Polyak K, He TC, Zhang L, Thiagalingam S, Kinzler KW and Vogelstein B . (1997). Mol. Cell, 1, 3–11.

  • Ho J and Benchimol S . (2003). Cell Death Differ., 10, 404–408.

  • Hobert O, Jallal B and Ullrich A . (1996). Mol. Cell. Biol., 16, 3066–3073.

  • Itahana K, Dimri G and Campisi J . (2001). Eur. J. Biochem., 268, 2784–2791.

  • Itahana K, Zou Y, Itahana Y, Martinez JL, Beausejour C, Jacobs JJ, Van Lohuizen M, Band V, Campisi J and Dimri GP . (2003). Mol. Cell. Biol., 23, 389–401.

  • Jacobs JJ and van Lohuizen M . (2002). Biochim. Biophys. Acta, 1602, 151–161.

  • Jones CA, Ng J, Peterson AJ, Morgan K, Simon J and Jones RS . (1998). Mol. Cell. Biol., 18, 2825–2834.

  • Karlseder J, Smogorzewska A and de Lange T . (2002). Science, 295, 2446–2449.

  • Kastan MB, Zhan Q, el-Deiry WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B and Fornace Jr AJ . (1992). Cell, 71, 587–597.

  • Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL and Shay JW . (1994). Science, 266, 2011–2015.

  • Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, Rubin MA and Chinnaiyan AM . (2003). Proc. Natl. Acad. Sci. USA, 100, 11606–11611.

  • Kouzarides T . (2002). Curr. Opin. Genet. Dev., 12, 198–209.

  • Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P and Reinberg D . (2002). Genes Dev., 16, 2893–2905.

  • Lin J, Chen J, Elenbaas B and Levine AJ . (1994). Genes Dev., 8, 1235–1246.

  • Maclean K, Rogan EM, Whitaker NJ, Chang AC, Rowe PB, Dalla-Pozza L, Symonds G and Reddel RR . (1994). Oncogene, 9, 719–725.

  • Mahmoudi T and Verrijzer CP . (2001). Oncogene, 20, 3055–3066.

  • Michael D and Oren M . (2002). Curr. Opin. Genet. Dev., 12, 53–59.

  • Narita M, Nunez S, Heard E, Lin AW, Hearn SA, Spector DL, Hannon GJ and Lowe SW . (2003). Cell, 113, 703–716.

  • Offer H, Erez N, Zurer I, Tang X, Milyavsky M, Goldfinger N and Rotter V . (2002). Carcinogenesis, 23, 1025–1032.

  • Ossovskaya VS, Mazo IA, Chernov MV, Chernova OB, Strezoska Z, Kondratov R, Stark GR, Chumakov PM and Gudkov AV . (1996). Proc. Natl. Acad. Sci. USA, 93, 10309–10314.

  • Raaphorst FM, van Kemenade FJ, Blokzijl T, Fieret E, Hamer KM, Satijn DP, Otte AP and Meijer CJ . (2000a). Am. J. Pathol., 157, 709–715.

  • Raaphorst FM, van Kemenade FJ, Fieret E, Hamer KM, Satijn DP, Otte AP and Meijer CJ . (2000b). J. Immunol., 164, 1–4.

  • Rhodes DR, Sanda MG, Otte AP, Chinnaiyan AM and Rubin MA . (2003). J. Natl. Cancer Inst., 95, 661–668.

  • Schwartz D and Rotter V . (1998). Semin. Cancer Biol., 8, 325–336.

  • Seluanov A, Gorbunova V, Falcovitz A, Sigal A, Milyavsky M, Zurer I, Shohat G, Goldfinger N and Rotter V . (2001). Mol. Cell. Biol., 21, 1552–1564.

  • Sewalt RG, van der Vlag J, Gunster MJ, Hamer KM, den Blaauwen JL, Satijn DP, Hendrix T, van Driel R and Otte AP . (1998). Mol. Cell. Biol., 18, 3586–3595.

  • Sharpless NE and DePinho RA . (2002). Cell, 110, 9–12.

  • Shaulian E, Zauberman A, Ginsberg D and Oren M . (1992). Mol. Cell. Biol., 12, 5581–5592.

  • Shay JW, Wright WE, Brasiskyte D and Van der Haegen BA . (1993). Oncogene, 8, 1407–1413.

  • Simon JA and Tamkun JW . (2002). Curr. Opin. Genet. Dev., 12, 210–218.

  • Stein GH, Drullinger LF, Soulard A and Dulic V . (1999). Mol. Cell. Biol., 19, 2109–2117.

  • Strahl BD and Allis CD . (2000). Nature, 403, 41–45.

  • Tarakhovsky A, Turner M, Schaal S, Mee PJ, Duddy LP, Rajewsky K and Tybulewicz VL . (1995). Nature, 374, 467–470.

  • Taylor WR, DePrimo SE, Agarwal A, Agarwal ML, Schonthal AH, Katula KS and Stark GR . (1999). Mol. Biol. Cell., 10, 3607–3622.

  • Taylor WR and Stark GR . (2001). Oncogene, 20, 1803–1815.

  • Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Hee Park S, Thompson T, Karsenty G, Bradley A and Donehower LA . (2002). Nature, 415, 45–53.

  • van Kemenade FJ, Raaphorst FM, Blokzijl T, Fieret E, Hamer KM, Satijn DP, Otte AP and Meijer CJ . (2001). Blood, 97, 3896–3901.

  • Vaziri H and Benchimol S . (1998). Curr. Biol., 8, 279–282.

  • Vousden KH and Lu X . (2002). Nat. Rev. Cancer, 2, 594–604.

  • Wang Q, Zambetti GP and Suttle DP . (1997). Mol. Cell. Biol., 17, 389–397.

  • Yeager TR, DeVries S, Jarrard DF, Kao C, Nakada SY, Moon TD, Bruskewitz R, Stadler WM, Meisner LF, Gilchrist KW, Newton MA, Waldman FM and Reznikoff CA . (1998). Genes Dev., 12, 163–174.

  • Zhang H, Pan KH and Cohen SN . (2003). Proc. Natl. Acad. Sci. USA, 100, 3251–3256.

Download references

Acknowledgements

We thank Dr Shelley Schwarzbaum for critical reading of the manuscript. This work was supported in part by grants from the Israel–USA Binational Science Foundation (BSF), the Kadoorie Foundation, and the Israeli Science Foundation (ISF). V Rotter is the incumbent of the Norman and Helen Asher Professorial Chair in Cancer Research at the Weizmann Institute.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Varda Rotter.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tang, X., Milyavsky, M., Shats, I. et al. Activated p53 suppresses the histone methyltransferase EZH2 gene. Oncogene 23, 5759–5769 (2004). https://doi.org/10.1038/sj.onc.1207706

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207706

Keywords

This article is cited by

Search

Quick links