Loss of histone deacetylase 4 causes segregation defects during mitosis of p53-deficient human tumor cells.
We investigated the role of histone deacetylase 4 (HDAC4) using RNA interference (RNAi) and knockout cells to specifically address its role in cell cycle progression in tumor and normal cells. Ablation of HDAC4 led to growth inhibition in human tumor cells but not to detectable effects in normal human dermal fibroblasts (NHDF) or myelopoietic progenitors. HDAC4-/+ or HDAC4-/- murine embryonic fibroblasts showed no detectable growth defects. On the other hand, HDAC4 RNAi in HeLa cells produced mitotic arrest followed by caspase-dependent apoptosis. Mitotically arrested cells showed chromosome segregation defects. Even though the growth of both p53-wild-type and p53-null tumor cells were affected by HDAC4 ablation, segregation defects were observed only in p53-null cells. HDAC4 associates with the PP2A-B56 regulatory subunit, which is known to be involved in chromosome segregation, and RNAi of either the structural subunit A or the regulatory subunit B56 of PP2A also caused chromosome segregation defects. We conclude that HDAC4 is required for cell cycle progression of tumor cells by multiple mechanisms, one of which seems to be specific to p53-deficient cells through chromosome segregation defects. On the contrary, HDAC4 is not required for the progression of NHDF. We therefore suggest that systemic selective interference with the expression or function of HDAC4 is expected to have a significant therapeutic window, in particular, for p53-deficient tumors.
Cadot
Bruno
B
Department of Oncology, IRBM-Merck Research Laboratories, Rome, Italy.
Brunetti
Mirko
M
Coppari
Sabina
S
Fedeli
Silvia
S
de Rinaldis
Emanuele
E
Dello Russo
Claudio
C
Gallinari
Paola
P
De Francesco
Raffaele
R
Steinkühler
Christian
C
Filocamo
Gessica
G
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D020090:Chromosome Segregation; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D045325:HCT116 Cells; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
D034741:RNA, Small Interfering; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C400300:HDAC4 protein, human; D006655:Histone Deacetylases