Transforming pathways unleashed by a HDAC2 mutation in human cancer.
Although disruption of histone modification patterns is a common hallmark of human cancer, our knowledge of the mechanistic role of histone-modifying enzymes in its generation is very limited. We have recently identified an inactivating mutation in the histone deacetylase-2 (HDAC2) in sporadic carcinomas with microsatellite instability and in tumors arising in individuals with hereditary nonpolyposis colorectal cancer syndrome. Since HDAC2 seems to be a central player in epigenetic gene repression, we wondered whether HDAC2-truncating mutations conferred a particular expression signature on these cancer cells. Using unsupervised clustering analysis in microsatellite-unstable colorectal cancer cell lines, we have found that HDAC2 mutant cells (RKO and Co115) show a characteristically different expression microarray signature from HDAC2 wild-type cells (HCT-116, SW48, HCT-15 and LoVo). HDAC2 mutant cells exhibit upregulation of tumor-promoting genes, such as those of tyrosine kinases, mediators of cell cycle progression and angiogenic factors. The overexpression of these genes is associated with a loss of HDAC2 recruitment and a gain of histone H4 hyperacetylation in their particular 5'-end promoters, as observed by chromatin immunoprecipitation. Transfection of wild-type HDAC2 in mutant cells reverted this epigenetic pattern by repressing the transforming genes in association with HDAC2 promoter occupancy. These results suggest a role for HDAC2 mutations in human tumorigenesis through the derepression of key genes from multiple cellular transformation pathways.
Ropero
S
S
Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Madrid, Spain.
Ballestar
E
E
Alaminos
M
M
Arango
D
D
Schwartz
S
S
Esteller
M
M
D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D016000:Cluster Analysis; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000235:genetics* / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D018895:Microsatellite Repeats; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D002843:Chromatin; D006657:Histones; D012097:Repressor Proteins; D014157:Transcription Factors; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases