Skip to main content

Thank you for visiting 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.

A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition


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 options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Biochemical and biological effects of HDAC2 mutations in human cancer.
Figure 2: The effect of HDAC inhibitors varies according to HDCA2 mutational status.
Figure 3: Immunohistochemistry of HDAC2 in sporadic colon tumors with microsatellite instability.


  1. Jones, P.A. & Baylin, S.B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3, 415–428 (2002).

    CAS  Article  Google Scholar 

  2. Feinberg, A.P. & Tycko, B. The history of cancer epigenetics. Nat. Rev. Cancer 4, 143–153 (2004).

    CAS  Article  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).

    CAS  Article  Google Scholar 

  4. Seligson, D.B. et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435, 1262–1266 (2005).

    CAS  Article  Google Scholar 

  5. Jenuwein, T. & Allis, C.D. Translating the histone code. Science 293, 1074–1080 (2001).

    CAS  Article  Google Scholar 

  6. Bannister, A.J. & Kouzarides, T. Histone methylation: recognizing the methyl mark. Methods Enzymol. 376, 269–288 (2004).

    CAS  Article  Google Scholar 

  7. Gayther, S.A. et al. Mutations truncating the EP300 acetylase in human cancers. Nat. Genet. 24, 300–303 (2000).

    CAS  Article  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).

    CAS  Article  Google Scholar 

  9. Lynch, H.T. & de la Chapelle, A. Hereditary colorectal cancer. N. Engl. J. Med. 348, 919–932 (2003).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  Google Scholar 

  13. Marks, P.A. & Jiang, X. Histone deacetylase inhibitors in programmed cell death and cancer therapy. Cell Cycle 4, 549–551 (2005).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  Google Scholar 

Download references


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


Corresponding author

Correspondence to Manel Esteller.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

FISH analysis of HDAC2. (PDF 40 kb)

Supplementary Fig. 2

HDAC2 analysis in endometrial cancer cell lines. (PDF 50 kb)

Supplementary Fig. 3

Biochemical and cellular effects of HDAC inhibitors according to the HDAC2 mutational status. (PDF 22 kb)

Supplementary Fig. 4

Inhibition of tumor growth by HDAC inhibitors according to HDAC2 mutational status. (PDF 37 kb)

Supplementary Fig. 5

Tumor suppressor effects of HDAC2 transfection in deficient cancer cells. (PDF 29 kb)

Supplementary Table 1

Primers used. (PDF 8 kb)

Rights and permissions

Reprints 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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing