[Anti-proliferative effect of histone deacetylase inhibitors on murine embryonic stem cells].
The effect of histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butirate (NaBut) on the proliferation of murine embryonic stem cells (MESC) was studied. Both agents suppressed the population growth and clonability of MESC. Flow cytometry analysis showed a decrease in the amount of S-phase cells upon treatment with HDAC inhibitors. TSA treatment caused a decrease in mRNA level of such positive cell cycle regulators as cyclins D1, A, c-myc, cdc25A, and induced transcription of negative regulators of the cell cycle--p21(Wafl) and p57(kip2). Also, HDAC inhibitors decreased the level of e2f-dependent transcription, with the concominant reduction of mRNA level of e2fl gene. HDAC inhibitors also affected the survival of MESC. A 2 day TSA treatment resulted in massive detachment and cell death, as confirmed by DNA laddering and MTT assay. Treatment with TSA for 2 and 5 days did not induce SAPbetaGAL, activity and p16(ink4a) transcription, i.e., characteristic features of senescent fibroblasts. In summary, HDAC inhibitors decrease the rate of proliferation affecting cell cycle and viability of MESC. We conclude that MESC are unable to realize a sustainable block of the cell cycle upon treatment with HDAC inhibitors.
Chuĭkin
I A
IA
Lianguzova
M S
MS
Pospelov
V A
VA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology*; D018816:Genes, cdc; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice
D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A