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Inhibitors of histone deacetylase arrest cell cycle and induce apoptosis in cervical carcinoma cells circumventing human papillomavirus oncogene expression

Oncogene volume 20, pages 4768–4776 (2001)Cite this article

Abstract

Histone deacetylase (HDAC) inhibitors sodium butyrate and trichostatin A arrest human papillomavirus (HPV)-positive carcinoma cells in G1 to S transition of the cell cycle, which is paralleled by an up-regulation of the cyclin-dependent kinase inhibitors (CKIs) p21CIP1 and p27KIP1 as well as the complete loss of cdk2 activity. Although HPV expression was hitherto thought to be required to maintain a proliferative phenotype of these cells, cdk2 suppression is achieved even in the presence of ongoing viral transcription. While CKIs normally cannot exert their cdk2-inhibitory function in the presence of the viral oncoprotein E7, co-immunoprecipitation experiments revealed that E7 binding is prevented. Increase of p27KIP1 correlates with down-regulation of p45SKP2, a component of the ubiquitin-protein ligase SCFSKP2 controlling the half-life of regulatory proteins during the cell cycle. HDAC inhibition also triggered an E7-dependent degradation of pRb, while the levels of E2F remained unaffected. The presence of free intracellular E2F and the concomitant up-regulation of CKIs during G1 arrest results in a ‘conflicting growth situation’, which finally renders the cells to undergo apoptosis. These data provide novel molecular insights into how the transforming potential of HPV can be bypassed and open new therapeutical perspectives for the treatment of cervical cancer.

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References

  • Almasan A, Yin Y, Kelly RE, Lee EY-HP, Bradley A, Li W, Bertino JR, Wahl GM . 1995 Proc. Natl. Acad. Sci. USA 92: 5436–5440

  • Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G . 1993 Genes Dev. 7: 812–821

  • Blomberg I, Hoffmann I . 1999 Mol. Cell. Biol. 19: 6183–6194

  • Boshart M, Gissmann L, Ikenberg H, Kleinheinz A, Scheurlen W, zur Hausen H . 1984 EMBO J. 3: 1151–1157

  • Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T . 1998 Nature 391: 597–601

  • Brehm A, Nielsen SJ, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T . 1999 EMBO J. 18: 2449–2458

  • Carnero A, Hannon GJ . 1998 Curr. Top. Microbiol. Immunol. 227: 43–55

  • Carrano AC, Eytan E, Hershko A, Pagano M . 1999 Nat. Cell Biol. 1: 193–199

  • Chomczynski P, Sacchi N . 1987 Anal. Biochem. 162: 156–159

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

  • Ercolani L, Florence B, Denaro M, Alexander M . 1988 J. Biol. Chem. 263: 15335–15341

  • Feinberg A, Vogelstein BA . 1984 Anal. Biochem. 137: 266–267

  • Finzer P, Soto U, Delius H, Patzelt A, Coy JF, Poustka A, zur Hausen H, Rösl F . 2000 Oncogene 19: 3235–3244

  • Haas-Kogan DA, Kogan SC, Levi D, Dazin P, T'Ang A, Fung YK, Israel MA . 1995 EMBO J. 14: 461–472

  • Hengst L, Reed SI . 1998 Curr. Top. Microbiol. Immunol. 227: 25–41

  • Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI, Weinberg RA . 1992 Cell 70: 993–1006

  • Hofmann F, Martelli F, Livingston DM, Wang Z . 1996 Genes Dev. 10: 2949–2959

  • Janson W, Brandner G, Siegel J . 1997 Oncogene 15: 1395–1406

  • Jones DL, Münger K . 1996 Semin. Cancer Biol. 7: 327–337

  • Lallemand F, Courilleau D, Sabbah M, Redeuilh G, Mester J . 1996 Biochem. Biophys. Res. Commun. 229: 163–169

  • Luo RX, Postigo AA, Dean DC . 1998 Cell 92: 463–473

  • Marti A, Wirbelauer C, Scheffner M, Krek W . 1999 Nat. Cell Biol. 1: 14–19

  • Martinez-Balbas MA, Bauer UM, Nielsen SJ, Brehm A, Kouzarides T . 2000 EMBO J 19: 662–671

  • Müller H, Bracken AP, Vernell R, Moroni MC, Christians F, Grassilli E, Prosperini E, Vigo E, Oliner JD, Helin K . 2001 Genes Dev. 15: 267–285

  • Nakayama K, Nagahama H, Minamishima Y, Matsumoto M, Nakamichi Il, Kitagawa K, Shirane M, Tsunematsu R, Tsukiyama T, Ishida N, Kitagawa M., Nakayama K-i, Hatakeyama S . 2000 EMBO J. 19: 2069–2081

  • Newmark HL, Lupton JR, Young CW . 1994 Cancer Lett. 78: 1–5

  • Pagano M, Pepperkok R, Verde F, Ansorge W, Draetta G . 1992 EMBO J. 11: 961–971

  • Park J-S, Kim E-J, Kwon H-J, Hwang E-S, Namkoong S-E, Um S-J . 2000 J. Biol. Chem. 275: 6764–6769

  • Parthun MR, Widom J, Gottschling DE . 1996 Cell 87: 85–94

  • Patel D, Huang S-M, Baglia LA, McCance DJ . 1999 EMBO J. 18: 5061–5072

  • Pines J, Hunter T . 1990 Nature 346: 760–763

  • Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massague J . 1994 Cell 78: 59–66

  • Rösl F, Kleine-Lowinski K, zur Hausen H . 1999 The possible role of chemokines in HPV-linked carcinogenesis. Rollins BJ. (ed.)Humana Press Inc., Totowa, NJ pp. 207–225

    Google Scholar 

  • Russo AA, Jeffrey PD, Patten AK, Massague J, Pavletich NP . 1996 Nature 382: 325–331

  • Sambucetti LC, Fischer DD, Zabludoff S, Kwon PO, Chamberlin H, Trogani N, Xu H, Cohen D . 1999 J. Biol. Chem. 274: 34940–34947

  • Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM . 1990 Cell 63: 1129–1136

  • Sherr CJ . 1993 Cell 73: 1059–1065

  • Sherr CJ . 1996 Science 274: 1672–1677

  • Siavoshian S, Blottiere HM, Cherbut C, Galmiche J-P . 1997 Biochem. Biophys. Res. Commun. 232: 169–172

  • Stoehr M, Vogt-Schaden M, Knobloch M, Vogel R, Futtermann G . 1978 Stain Technol. 55: 205–215

  • Sutterlüty H, Chatelain E, Marti A, Wirbelauer C, Senften M, Müller U, Krek W . 1999 Nat. Cell Biol. 1: 207–214

  • Tommasino M, Adamczewski JP, Carlotti F, Barth CF, Manetti R, Contorni M, Cavalieri F, Hunt T, Crawford L . 1993 Oncogene 8: 195–202

  • Wade PA, Pruss D, Wolffe AP . 1997 Trends Biochem. Sci. 22: 128–132

  • von Knebel Doeberitz M, Oltersdorf T, Schwarz E, Gissmann L . 1988 Cancer Res. 48: 3780–3786

  • Weinberg RA . 1995 Cell 81: 323–330

  • Workman JL, Kingston RE . 1998 Annu. Rev. Biochem. 67: 545–579

  • Wu C . 1997 J. Biol. Chem. 272: 28171–28174

  • Xiao H, Hasegawa T, Isobe K-I . 2000 J. Biol. Chem. 275: 1371–1376

  • Zerfass K, Schulze A, Spitkovsky D, Friedman V, Henglein B, Jansen-Dürr P . 1995 J. Virol. 69: 6389–6399

  • Zerfass-Thome K, Schulze A, Zwerschke W, Vogt B, Helin K, Bartek J, Henglein B, Jansen-Dürr P . 1997 J. Virol. 17: 407–415

  • Zhang H, Hannon GJ, Beach D . 1994 Genes Dev. 8: 1750–1758

  • Zhang H, Kobayashi R, Galaktionov K, Beach D . 1995 Cell 82: 915–925

  • Zur Hausen H . 2000 J. Natl. Cancer Inst. 92: 690–698

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Acknowledgements

The authors are grateful to our colleagues for providing plasmid probes and biochemical reagents. We are also grateful to N Whitaker (University of New South Wales, Sydney, Australia) for giving us the HPV16-immortalized human keratinocytes. The excellent technical support of Nadine Seibert and Christina Weber is appreciated. We also thank Michael Stoehr (DKFZ, Heidelberg) for his help in FACS analysis and Leslie Thomas for carefully reading the manuscript.

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  1. Abteilung Tumorvirus-Immunologie, Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Angewandte Tumorvirologie, Im Neuenheimer Feld 242, Heidelberg, 69120, Germany

    Patrick Finzer, Christian Kuntzen, Ubaldo Soto, Harald zur Hausen & Frank Rösl

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  1. Patrick Finzer
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  2. Christian Kuntzen
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Correspondence to Frank Rösl.

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Finzer, P., Kuntzen, C., Soto, U. et al. Inhibitors of histone deacetylase arrest cell cycle and induce apoptosis in cervical carcinoma cells circumventing human papillomavirus oncogene expression. Oncogene 20, 4768–4776 (2001). https://doi.org/10.1038/sj.onc.1204652

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