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

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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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.

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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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Correspondence to Manel Esteller.

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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)

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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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