title: 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.
authors.affiliation: Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), 28029 Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ropero
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
authors.forename: Richard
authors.initials: R
authors.lastname: Hamelin
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Manuel
authors.initials: M
authors.lastname: Boix-Chornet
authors.forename: Rosalia
authors.initials: R
authors.lastname: Caballero
authors.forename: Miguel
authors.initials: M
authors.lastname: Alaminos
authors.forename: Fernando
authors.initials: F
authors.lastname: Setien
authors.forename: Maria F
authors.initials: MF
authors.lastname: Paz
authors.forename: Michel
authors.initials: M
authors.lastname: Herranz
authors.forename: Jose
authors.initials: J
authors.lastname: Palacios
authors.forename: Diego
authors.initials: D
authors.lastname: Arango
authors.forename: Torben F
authors.initials: TF
authors.lastname: Orntoft
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: Simó
authors.initials: S
authors.lastname: Schwartz
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D002453:Cell Cycle; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D019075:Electrophoresis, Capillary; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases