Skip to main content
SpringerLink
Log in

Cell Cycle Targets of Histone Deacetylase Inhibitors

  • Chapter
Histone Deacetylases

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

  • 713 Accesses

Abstract

Histone deacetylase inhibitors (HDIs) can potentially affect a broad spectrum of cellular events by stabilizing the acetylation of an increasing number of proteins. One of the most notable outcomes is the effect on cell cycle progression almost universally observed following treatment with this class of drugs. These effects are either G1 or G2/M phase cell cycle arrests, and mitosis is also adversely affected. Histone hyperacetylation and consequent transcriptional changes contribute directly to the G1 phase arrest, but the hyperacetylated targets for the G2 phase arrest and mitotic defects are yet to be absolutely identified. These cell cycle effects are the basis of the antiproliferative activity and tumor cell selectivity of these drugs, properties that potentially make them highly effective anticancer drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Abbreviations

ATM:

Ataxia telangiectasia mutated

INK4:

Inhibitor of cdk4

CTP:

Cytidine triphosphate

ATM/ATR:

ATR is ATM and RAD3 related

Gadd45:

Growth arrest and DNA damage-inducible

CENP-A:

Centromere protein A

SUV39H1:

Suppressor of variegation 39 Human 1

References

  1. Gray-Bablin J, Zalvide J, Fox MP, Knickerbocker C J, DeCaprio JA, Keyomarsi K. Cyclin E, a redundant cyclin in breast cancer. Proc Natl Acad Sci U S A 1996;93:15,215–15,220.

    Article  PubMed  CAS  Google Scholar 

  2. Sherr CJ. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res 2000;60:3689–3695.

    PubMed  CAS  Google Scholar 

  3. Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol 1995;15:2612–2624.

    PubMed  CAS  Google Scholar 

  4. Pagano M, Pepperkok R, Verde F, Ansorge W, Draetta G. Cyclin A is required at two points in the human cell cycle. EMBO J 1992; 11:961–971.

    PubMed  CAS  Google Scholar 

  5. Strausfeld UP, Howell M, Descombes P, et al. Both cyclin A and cyclin E have Sphase promoting (SPF) activity in Xenopus egg extracts. J Cell Sci 1996;109:1555–1563.

    CAS  Google Scholar 

  6. Sambucetti LC, Fischer DD, Zabludoff S, et al. Histone deacetylase inhibition selectively alters the activity and expression of cell cycle proteins leading to specific chromatin acetylation and antiproliferative effects. J Biol Chem 1999;274:34,940–34,947.

    Article  PubMed  CAS  Google Scholar 

  7. Qiu L, Burgess A, Fairlie DP, Leonard H, Parsons PG, Gabrielli BG. Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells. Mol Biol Cell 2000; 11:2069–2083.

    PubMed  CAS  Google Scholar 

  8. Sandor V, Senderowicz A, Mertins S, et al. P21-dependent g(1)arrest with down-regulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. Br J Cancer 2000;83:817–825.

    Article  PubMed  CAS  Google Scholar 

  9. Huang L, Sowa Y, Sakai T, Pardee AB. Activation of the p21WAF1/CIP1 promoter independent of p53 by the histone deacetylase inhibitor suberoy-lanilide hydroxamic acid (SAHA) through the Sp1 sites. Oncogene 2000;19: 5712–5719.

    Article  PubMed  CAS  Google Scholar 

  10. Xiao H, Hasegawa T, Isobe K. p300 collaborates with Sp1 nd Sp3 in p21(waf1/cip1) promoter activation induced by histone deacetylase inhibitor. J Biol Chem 2000;275:1371–1376.

    Article  PubMed  CAS  Google Scholar 

  11. Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci U S A 2000;97:10,014–10,019.

    Article  PubMed  CAS  Google Scholar 

  12. Kim YK, Han JW, Woo YN, et al. Expression of p21(WAF1/Cip1) through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase-PKC epsilon signaling pathway. Oncogene 2003;22:6023–6031.

    Article  PubMed  CAS  Google Scholar 

  13. Gui CY, Ngo L, Xu WS, Richon VM, Marks PA. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC 1. Proc Natl Acad Sci U S A 2004;101:1241–1246.

    Article  PubMed  CAS  Google Scholar 

  14. Canman CE, Lim DS, Cimprich KA, et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 1998;281:1677–1679.

    Article  PubMed  CAS  Google Scholar 

  15. Khanna KK, Keating KE, Kozlov S, et al. ATM associates with and phosphory-lates p53: mapping the region of interaction. Nat Genet 1998;20:398–400.

    Article  PubMed  CAS  Google Scholar 

  16. Ju R, Muller MT. Histone deacetylase inhibitors activate p21(WAF1) expression via ATM. Cancer Res 2003;63:2891–2897.

    PubMed  CAS  Google Scholar 

  17. Archer SY, Meng S, Shei A, Hodin RA. p21(WAF1) is required for butyrate-mediated growth inhibition of human colon cancer cells. Proc Natl Acad Sci USA 1998;95:6791–6796.

    Article  PubMed  CAS  Google Scholar 

  18. Burgess AJ, Pavey S, Warrener R, et al. Up-regulation of p21(WAF1/CIP1) by histone deacetylase inhibitors reduces their cytotoxicity. Mol Pharmacol 2001;60:828–837.

    PubMed  CAS  Google Scholar 

  19. Hitomi T, Matsuzaki Y, Yokota T, Takaoka Y, Sakai T. p15(INK4b) in HDAC inhibitor-induced growth arrest. FEBS Lett 2003;554:347–350.

    Article  PubMed  CAS  Google Scholar 

  20. Sato N, Fukushima N, Maitra A, et al. Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Histone acetylation-mediated regulation of genes in leukaemic cells. 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. Cancer Res 2003;63:3735–3742.

    PubMed  CAS  Google Scholar 

  21. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci U S A 2004;101:540–545.

    Article  PubMed  CAS  Google Scholar 

  22. Yokota T, Matsuzaki Y, Miyazawa K, Zindy F, Roussel MF, Sakai T. Histone deacetylase inhibitors activate INK4d gene through Sp1 site in its promoter. Oncogene 2004;26:26.

    Google Scholar 

  23. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 1995;9:1149–1163.

    Article  PubMed  CAS  Google Scholar 

  24. McConnell BB, Gregory FJ, Stott FJ, Hara E, Peters G. Induced expression of p16(INK4a) inhibits both CDK4-and CDK2-associated kinase activity by reas-sortment of cyclin-CDK-inhibitor complexes. Mol Cell Biol 1999;19:1981–1989.

    PubMed  CAS  Google Scholar 

  25. Kim YB, Lee KH, Sugita K, Yoshida M, Horinouchi S. Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase. Oncogene 1999;18:2461–2470.

    Article  PubMed  CAS  Google Scholar 

  26. Wharton W, Savell J, Cress WD, Seto E, Pledger WJ. Inhibition of mitogenesis in Balb/c-3T3 cells by trichostatin A. Multiple alterations in the induction and activation of cyclin-cyclin-dependent kinase complexes. J Biol Chem 2000;275: 33,981–33,987.

    Article  PubMed  CAS  Google Scholar 

  27. 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.

    PubMed  CAS  Google Scholar 

  28. Warrener R, Beamish H, Burgess A, et al. Tumor cell-selective cytotoxicity by targeting cell cycle checkpoints. FASEB J 2003;17:1550–1552.

    PubMed  CAS  Google Scholar 

  29. Bernhard D, Ausserlechner MJ, Tonko M, et al. Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts. FASEB J 1999;13:1991–2001.

    PubMed  CAS  Google Scholar 

  30. Ruefli AA, Ausserlechner MJ, Bernhard D, 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 U S A 2001;98:10,833–10,838.

    Article  PubMed  CAS  Google Scholar 

  31. Peart MJ, Tainton KM, Ruefli AA, et al. Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. Cancer Res 2003;63:4460–4471.

    PubMed  CAS  Google Scholar 

  32. Vrana JA, Decker RH, Johnson CR, et al. Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53. Oncogene 1999;18:7016–7025.

    Article  PubMed  CAS  Google Scholar 

  33. Rosato RR, Wang Z, Gopalkrishnan RV, Fisher PB, Grant S. Evidence of a functional role for the cyclin-dependent kinase-inhibitor p21WAF1/CIP1/MDA6 in promoting differentiation and preventing mitochondrial dysfunction and apoptosis induced by sodium butyrate in human myelomonocytic leukemia cells (U937). IntJ Oncol 2001;19:181–191.

    CAS  Google Scholar 

  34. Rahmani M, Yu C, Dai Y, et al. Coadministration of the heat shock protein 90 antagonist 17-allylamino-17-demethoxygeldanamycin with suberoylanilide hydroxamic acid or sodium butyrate synergistically induces apoptosis in human leukemia cells. Cancer Res 2003;63:8420–8427.

    PubMed  CAS  Google Scholar 

  35. Rosato RR, Almenara JA, Yu C, Grant S. Evidence of a functional role for p21WAF1/CIP1 down-regulation in synergistic antileukemic interactions between the histone deacetylase inhibitor sodium butyrate and flavopiridol. Mol Pharmacol 2004;65:571–581.

    Article  PubMed  CAS  Google Scholar 

  36. Rahmani M, Yu C, Reese E, et al. Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21(CIP1/WAF1) induction rather than AKT inhibition. Oncogene 2003;22:6231–6242.

    Article  PubMed  CAS  Google Scholar 

  37. Rosato RR, Almenara JA, Grant S. The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. Cancer Res 2003;63:3637–3645.

    PubMed  CAS  Google Scholar 

  38. Suzuki A, Tsutomi Y, Yamamoto N, Shibutani T, Akahane K. Mitochondrial regulation of cell death: mitochondria are essential for procaspase 3-p21 complex formation to resist Fas-mediated cell death. Mol Cell Biol 1999;19:3842–3847.

    PubMed  CAS  Google Scholar 

  39. Park JA, Kim KW, Kim SI, Lee SK. Caspase 3 specifically cleaves p21WAF1/CIP1 in the earlier stage of apoptosis in SK-HEP-1 human hepatoma cells. Eur JBiochem 1998;257:242–248.

    Article  CAS  Google Scholar 

  40. Burgess A, Ruefli A, Beamish H, et al. Histone deacetylase inhibitors specifically kill nonproliferating tumour cells. Oncogene 2004;23:6693–6701.

    Article  PubMed  CAS  Google Scholar 

  41. Qiu L, Kelso MJ, Hansen C, West ML, Fairlie DP, Parsons PG. Anti-tumour activity in vitro and in vivo of selective differentiating agents containing hydroxamate. Br J Cancer 1999;80:1252–1258.

    Article  PubMed  CAS  Google Scholar 

  42. Krauer KG, Burgess A, Buck M, Flanagan J, Sculley TB, Gabrielli B. The EBNA-3 gene family proteins disrupt the G2/M checkpoint. Oncogene 2004;23: 1342–1353.

    Article  PubMed  CAS  Google Scholar 

  43. Mitsiades N, Mitsiades CS, Richardson PG, et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Molecular sequelae of histone deacetylase inhibition in human malignant B cells 2003;101: 4055–4062.

    CAS  Google Scholar 

  44. Lallemand F, Courilleau D,Buquet-FagotC,AtfiA,MontagneMN,Mester J. Sodium butyrate induces G2 arrest in the human breast cancer cells MDA-MB-231 and renders them competent for DNA rereplication. Exp Cell Res 1999;247:432–440.

    Article  PubMed  CAS  Google Scholar 

  45. Jin S, Antinore MJ, Lung FD, et al. The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression. J Biol Chem 2000;275: 16,602–16,608.

    Article  PubMed  CAS  Google Scholar 

  46. Hirose T, Sowa Y, Takahashi S, et al. p53-independent induction of Gadd45 by histone deacetylase inhibitor: coordinate regulation by transcription factors Oct-1 andNF-Y. Oncogene 2003;22:7762–7773.

    Article  PubMed  CAS  Google Scholar 

  47. Taddei A, Maison C, Roche D, Almouzni G. Reversible disruption of pericentric heterochromatin and centromere function by inhibiting deacetylases. Nat Cell Biol 2001;3:114–120.

    Article  PubMed  CAS  Google Scholar 

  48. Shin HJ, Baek KH, Jeon AH, et al. Inhibition of histone deacetylase activity increases chromosomal instability by the aberrant regulation of mitotic checkpoint activation. Oncogene 2003;22:3853–3858.

    Article  PubMed  CAS  Google Scholar 

  49. Cimini D, Mattiuzzo M, Torosantucci L, Degrassi F. Histone hyperacetylation in mitosis prevents sister chromatid separation and produces chromosome segregation defects. Mol Biol Cell 2003;14:3821–3833.

    Article  PubMed  CAS  Google Scholar 

  50. Musacchio A, Hardwick KG. The spindle checkpoint: structural insights into dynamic signalling. Nat Rev Mol Cell Biol 2002;3:731–741.

    Article  PubMed  CAS  Google Scholar 

  51. Sobel RE, Cook RG, Perry CA, Annunziato AT, Allis CD. Conservation of deposition-related acetylation sites in newly synthesized histones H3 and H4. Proc NatlAcadSciUS A 1995;92:1237–1241.

    Article  CAS  Google Scholar 

  52. Taddei A, Roche D, Sibarita JB, Turner BM, Almouzni G. Duplication and maintenance of heterochromatin domains. J Cell Biol 1999;147:1153–1166.

    Article  PubMed  CAS  Google Scholar 

  53. Mello JA, Almouzni G. The ins and outs of nucleosome assembly. Curr Opin Genet Dev 2001;11:136–141.

    Article  PubMed  CAS  Google Scholar 

  54. Mackay AM, Ainsztein AM, Eckley DM, Earnshaw WC. A dominant mutant of inner centromere protein (INCENP), a chromosomal protein, disrupts prometaphase congression and cytokinesis. J Cell Biol 1998;140:991–1002.

    Article  PubMed  CAS  Google Scholar 

  55. Nishihashi A, Haraguchi T, Hiraoka Y, et al. CENP-I is essential for centromere function in vertebrate cells. Dev Cell 2002;2:463–476.

    Article  PubMed  CAS  Google Scholar 

  56. Schaar BT, Chan GK, Maddox P, Salmon ED, Yen TJ. CENP-E function at kinetochores is essential for chromosome alignment. J Cell Biol 1997; 139: 1373–1382.

    Article  PubMed  CAS  Google Scholar 

  57. Taylor SS, McKeon F. Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell 1997;89:727–735.

    Article  PubMed  CAS  Google Scholar 

  58. Prigent C, Dimitrov S. Phosphorylation of serine 10 in histone H3, what for? J Cell Sci 2003;116:3677–3685.

    Article  PubMed  CAS  Google Scholar 

  59. Ekwall K, Olsson T, Turner BM, Cranston G, Allshire RC. Transient inhibition of histone deacetylation alters the structural and functional imprint at fission yeast centromeres. Cell 1997;91:1021–1032.

    Article  PubMed  CAS  Google Scholar 

  60. Rea S, Eisenhaber F, O’Carroll D, et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 2000;406:593–599.

    Article  PubMed  CAS  Google Scholar 

  61. Bannister A J, Zegerman P, Partridge JF, et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 2001;410:120–124.

    Article  PubMed  CAS  Google Scholar 

  62. Mellone BG, Ball L, Suka N, Grunstein MR, Partridge JF, Allshire RC. Centromere silencing and function in fission yeast is governed by the amino terminus of histone H3. Curr Biol 2003;13:1748–1757.

    Article  PubMed  CAS  Google Scholar 

  63. David G, Turner GM, Yao Y, Protopopov A, DePinho RA. mSin3-associated protein, mSds3, is essential for pericentric heterochromatin formation and chromosome segregation in mammalian cells. Genes Dev 2003;17:2396–2405.

    Article  PubMed  CAS  Google Scholar 

  64. Silverstein RA, Richardson W, Levin H, Allshire R, Ekwall K. A new role for the transcriptional corepressor SIN3; regulation of centromeres. Curr Biol 2003;13:68–72.

    Article  PubMed  CAS  Google Scholar 

  65. Dillon N, Festenstein R, Cheung WL, Briggs SD, Allis CD. Unravelling heterochromatin: competition between positive and negative factors regulates accessibility. Acetylation and chromosomal functions. Trends Genet 2002;18:252–258.

    Article  PubMed  CAS  Google Scholar 

  66. Jenuwein T, Allis CD. Translating the histone code. Science 2001;293:1074–1080.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Epithelial Pathobiology Group, Centre for Immunology and Cancer Research, University of Queensland Department of Medicine, Princess Alexandra Hospital, Brisbane, Queensland, Australia

    Brian Gabrielli PhD

Authors
  1. Brian Gabrielli PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA

    Eric Verdin MD

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Gabrielli, B. (2006). Cell Cycle Targets of Histone Deacetylase Inhibitors. In: Verdin, E. (eds) Histone Deacetylases. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59745-024-3:299

Download citation

Publish with us

Policies and ethics

Search

Navigation