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

• Published in: Nature genetics Vol. 38; no. 5; pp. 566 - 569
• Main Authors: Esteller, Manel, Ropero, Santiago, Fraga, Mario F, Ballestar, Esteban, Hamelin, Richard, Yamamoto, Hiroyuki, Boix-Chornet, Manuel, Caballero, Rosalia, Alaminos, Miguel, Setien, Fernando, Paz, Maria F, Herranz, Michel, Palacios, Jose, Arango, Diego, Orntoft, Torben F, Aaltonen, Lauri A, Schwartz, Simó
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-05-2006
• Subjects: Amino Acid Sequence; Antineoplastic Agents - therapeutic use; Apoptosis; Biological and medical sciences; Cancer; Cell Cycle; Colorectal carcinoma; Drug Resistance, Neoplasm - genetics; Electrophoresis, Capillary; Enzymatic activity; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene expression; Genetics of eukaryotes. Biological and molecular evolution; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histone Deacetylases - chemistry; Histone Deacetylases - genetics; Humans; Inhibitor drugs; Molecular Sequence Data; Mutation; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - chemistry; Repressor Proteins - genetics; RNA, Small Interfering; Human; Resistance; Inhibition; Mutation; Malignant tumor; Histone
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1773

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.