A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition (original) (raw)

Nature Genetics volume 38, pages 566–569 (2006)Cite this article

Abstract

Disruption of histone acetylation patterns is a common feature of cancer cells, but very little is known about its genetic basis. We have identified truncating mutations in one of the primary human histone deacetylases, HDAC2, in sporadic carcinomas with microsatellite instability and in tumors arising in individuals with hereditary nonpolyposis colorectal cancer syndrome. The presence of the HDAC2 frameshift mutation causes a loss of HDAC2 protein expression and enzymatic activity and renders these cells more resistant to the usual antiproliferative and proapoptotic effects of histone deacetylase inhibitors. As such drugs may serve as therapeutic agents for cancer, our findings support the use of HDAC2 mutational status in future pharmacogenetic treatment of these individuals.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

References

  1. Jones, P.A. & Baylin, S.B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3, 415–428 (2002).
    Article CAS Google Scholar
  2. Feinberg, A.P. & Tycko, B. The history of cancer epigenetics. Nat. Rev. Cancer 4, 143–153 (2004).
    Article CAS Google Scholar
  3. Fraga, M.F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat. Genet. 37, 391–400 (2005).
    Article CAS Google Scholar
  4. Seligson, D.B. et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435, 1262–1266 (2005).
    Article CAS Google Scholar
  5. Jenuwein, T. & Allis, C.D. Translating the histone code. Science 293, 1074–1080 (2001).
    Article CAS Google Scholar
  6. Bannister, A.J. & Kouzarides, T. Histone methylation: recognizing the methyl mark. Methods Enzymol. 376, 269–288 (2004).
    Article CAS Google Scholar
  7. Gayther, S.A. et al. Mutations truncating the EP300 acetylase in human cancers. Nat. Genet. 24, 300–303 (2000).
    Article CAS Google Scholar
  8. Ionov, Y., Matsui, S. & Cowell, J.K. A role for p300/CREB binding protein genes in promoting cancer progression in colon cancer cell lines with microsatellite instability. Proc. Natl. Acad. Sci. USA 101, 1273–1278 (2004).
    Article CAS Google Scholar
  9. Lynch, H.T. & de la Chapelle, A. Hereditary colorectal cancer. N. Engl. J. Med. 348, 919–932 (2003).
    Article CAS Google Scholar
  10. Herman, J.G. et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc. Natl. Acad. Sci. USA 95, 6870–6875 (1998).
    Article CAS Google Scholar
  11. Markowitz, S. et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995).
    Article CAS Google Scholar
  12. Rampino, N. et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275, 967–969 (1997).
    Article CAS Google Scholar
  13. Marks, P.A. & Jiang, X. Histone deacetylase inhibitors in programmed cell death and cancer therapy. Cell Cycle 4, 549–551 (2005).
    Article CAS Google Scholar
  14. Archer, S.Y., Meng, S., Shei, A. & Hodin, R.A. p21(WAF1) is required for butyrate-mediated growth inhibition of human colon cancer cells. Proc. Natl. Acad. Sci. USA 95, 6791–6796 (1998).
    Article CAS Google Scholar
  15. Myzak, M.C. et al. Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apcmin mice. FASEB J. 20, 506–508 (2006).
    Article CAS Google Scholar
  16. Lagger, G. et al. Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J. 21, 2672–2681 (2002).
    Article CAS Google Scholar
  17. Wang, D.F., Helquist, P., Wiech, N.L. & Wiest, O. Toward selective histone deacetylase inhibitor design: homology modeling, docking studies, and molecular dynamics simulations of human class I histone deacetylases. J. Med. Chem. 48, 6936–6947 (2005).
    Article CAS Google Scholar
  18. Turner, B.M. & Fellows, G. Specific antibodies reveal ordered and cell-cycle-related use of histone-H4 acetylation sites in mammalian cells. Eur. J. Biochem. 179, 131–139 (1989).
    Article CAS Google Scholar
  19. Fraga, M.F. et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl. Acad. Sci. USA 102, 10604–10609 (2005).
    Article CAS Google Scholar
  20. Espada, J. et al. Human DNA methyltransferase 1 is required for maintenance of the histone H3 modification pattern. J. Biol. Chem. 279, 37175–37184 (2004).
    Article CAS Google Scholar

Download references

Acknowledgements

This work was supported, in part, by the Health and Science Departments of the Spanish Government and the Spanish Association Against Cancer (AECC).

Author information

Authors and Affiliations

  1. Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Madrid, 28029, Spain
    Santiago Ropero, Mario F Fraga, Esteban Ballestar, Manuel Boix-Chornet, Rosalia Caballero, Miguel Alaminos, Fernando Setien, Maria F Paz, Michel Herranz & Manel Esteller
  2. INSERM U434, Centre d'Etude du Polymorphisme Humain, Paris, 75010, France
    Richard Hamelin
  3. First Department of Internal Medicine, Sapporo Medical University, Sapporo, 060-8543, Japan
    Hiroyuki Yamamoto
  4. Laboratory of Breast and Gynaecological Cancer, Spanish National Cancer Centre (CNIO), Madrid, 28029, Spain
    Jose Palacios
  5. Molecular Oncology and Aging Research, Centre d'Investigacions en Bioquimica i Biologia Molecular, Hospital Universitari Vall d'Hebron, Barcelona, 08035, Catalonia, Spain
    Diego Arango & Simó Schwartz Jr
  6. Department of Clinical Biochemistry, Molecular Diagnostic Laboratory, Aarhus University Hospital/Skejby, Brendstrupgaardsvej 100, Aarhus N, DK-8200, Denmark
    Torben F Orntoft
  7. Department of Medical Genetics, Haartmaninkatu 8, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
    Lauri A Aaltonen

Authors

  1. Santiago Ropero
    You can also search for this author inPubMed Google Scholar
  2. Mario F Fraga
    You can also search for this author inPubMed Google Scholar
  3. Esteban Ballestar
    You can also search for this author inPubMed Google Scholar
  4. Richard Hamelin
    You can also search for this author inPubMed Google Scholar
  5. Hiroyuki Yamamoto
    You can also search for this author inPubMed Google Scholar
  6. Manuel Boix-Chornet
    You can also search for this author inPubMed Google Scholar
  7. Rosalia Caballero
    You can also search for this author inPubMed Google Scholar
  8. Miguel Alaminos
    You can also search for this author inPubMed Google Scholar
  9. Fernando Setien
    You can also search for this author inPubMed Google Scholar
  10. Maria F Paz
    You can also search for this author inPubMed Google Scholar
  11. Michel Herranz
    You can also search for this author inPubMed Google Scholar
  12. Jose Palacios
    You can also search for this author inPubMed Google Scholar
  13. Diego Arango
    You can also search for this author inPubMed Google Scholar
  14. Torben F Orntoft
    You can also search for this author inPubMed Google Scholar
  15. Lauri A Aaltonen
    You can also search for this author inPubMed Google Scholar
  16. Simó Schwartz Jr
    You can also search for this author inPubMed Google Scholar
  17. Manel Esteller
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toManel Esteller.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Ropero, S., Fraga, M., Ballestar, E. et al. A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition.Nat Genet 38, 566–569 (2006). https://doi.org/10.1038/ng1773

Download citation