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.
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References
Jones, P.A. & Baylin, S.B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3, 415–428 (2002).
Feinberg, A.P. & Tycko, B. The history of cancer epigenetics. Nat. Rev. Cancer 4, 143–153 (2004).
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).
Seligson, D.B. et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435, 1262–1266 (2005).
Jenuwein, T. & Allis, C.D. Translating the histone code. Science 293, 1074–1080 (2001).
Bannister, A.J. & Kouzarides, T. Histone methylation: recognizing the methyl mark. Methods Enzymol. 376, 269–288 (2004).
Gayther, S.A. et al. Mutations truncating the EP300 acetylase in human cancers. Nat. Genet. 24, 300–303 (2000).
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).
Lynch, H.T. & de la Chapelle, A. Hereditary colorectal cancer. N. Engl. J. Med. 348, 919–932 (2003).
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).
Markowitz, S. et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995).
Rampino, N. et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275, 967–969 (1997).
Marks, P.A. & Jiang, X. Histone deacetylase inhibitors in programmed cell death and cancer therapy. Cell Cycle 4, 549–551 (2005).
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).
Myzak, M.C. et al. Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apcmin mice. FASEB J. 20, 506–508 (2006).
Lagger, G. et al. Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J. 21, 2672–2681 (2002).
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).
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).
Fraga, M.F. et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl. Acad. Sci. USA 102, 10604–10609 (2005).
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).
Acknowledgements
This work was supported, in part, by the Health and Science Departments of the Spanish Government and the Spanish Association Against Cancer (AECC).
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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)
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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
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DOI: https://doi.org/10.1038/ng1773
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