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.
Ropero
Santiago
S
Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), 28029 Madrid, Spain.
Fraga
Mario F
MF
Ballestar
Esteban
E
Hamelin
Richard
R
Yamamoto
Hiroyuki
H
Boix-Chornet
Manuel
M
Caballero
Rosalia
R
Alaminos
Miguel
M
Setien
Fernando
F
Paz
Maria F
MF
Herranz
Michel
M
Palacios
Jose
J
Arango
Diego
D
Orntoft
Torben F
TF
Aaltonen
Lauri A
LA
Schwartz
Simó
S
Esteller
Manel
M
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*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases