Role for histone deacetylase 1 in human tumor cell proliferation.
Posttranslational modifications of core histones are central to the regulation of gene expression. Histone deacetylases (HDACs) repress transcription by deacetylating histones, and class I HDACs have a crucial role in mouse, Xenopus laevis, zebra fish, and Caenorhabditis elegans development. The role of individual class I HDACs in tumor cell proliferation was investigated using RNA interference-mediated protein knockdown. We show here that in the absence of HDAC1 cells can arrest either at the G(1) phase of the cell cycle or at the G(2)/M transition, resulting in the loss of mitotic cells, cell growth inhibition, and an increase in the percentage of apoptotic cells. On the contrary, HDAC2 knockdown showed no effect on cell proliferation unless we concurrently knocked down HDAC1. Using gene expression profiling analysis, we found that inactivation of HDAC1 affected the transcription of specific target genes involved in proliferation and apoptosis. Furthermore, HDAC2 downregulation did not cause significant changes compared to control cells, while inactivation of HDAC1, HDAC1 plus HDAC2, or HDAC3 resulted in more distinct clusters. Loss of these HDACs might impair cell cycle progression by affecting not only the transcription of specific target genes but also other biological processes. Our data support the idea that a drug targeting specific HDACs could be highly beneficial in the treatment of cancer.
Senese
Silvia
S
European Institute of Oncology, Department of Experimental Oncology, Via Ripamonti 435, 20141 Milan, Italy.
Zaragoza
Katrin
K
Minardi
Simone
S
Muradore
Ivan
I
Ronzoni
Simona
S
Passafaro
Alfonso
A
Bernard
Loris
L
Draetta
Giulio F
GF
Alcalay
Myriam
M
Seiser
Christian
C
Chiocca
Susanna
S
D000107:Acetylation; D016923:Cell Death; D002455:Cell Division; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D016000:Cluster Analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016193:G1 Phase; D016195:G2 Phase; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000172:deficiency / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D000099186:Histone Deacetylase 3
D050759:Cyclin-Dependent Kinase Inhibitor p21; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D006657:Histones; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C110550:HDAC1 protein, human; C533424:Hdac2 protein, mouse