Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent.
Human diploid fibroblasts (HDF) complete a limited number of cell divisions before entering a growth arrest state that is termed replicative senescence. Two histone deacetylase inhibitors, sodium butyrate and trichostatin A, dramatically reduce the HDF proliferative life span in a manner that is dependent on one or more cell doublings in the presence of these agents. Cells arrested and subsequently released from histone deacetylase inhibitors display markers of senescence and exhibit a persistent G1 block but remain competent to initiate a round of DNA synthesis in response to simian virus 40 T antigen. Average telomere length in prematurely arrested cells is greater than in senescent cells, reflecting a lower number of population doublings completed by the former. Taken together, these results support the view that one component of HDF senescence mimics a cell cycle-dependent drift in differentiation state and that propagation of HDF in histone deacetylase inhibitors accentuates this component.
Ogryzko
V V
VV
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, Bethesda, Maryland 20892-2753, USA.
Hirai
T H
TH
Russanova
V R
VR
Barbie
D A
DA
Howard
B H
BH
D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000502:physiology; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D006367:HeLa Cells / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000502:physiology; D016615:Telomere / Q000648:ultrastructure; D014162:Transfection
D000957:Antigens, Viral, Tumor; D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016160:Retinoblastoma Protein; D020148:Butyric Acid; C012589:trichostatin A; D006655:Histone Deacetylases