Inhibition of NF-kappaB activation by the histone deacetylase inhibitor 4-Me2N-BAVAH induces an early G1 cell cycle arrest in primary hepatocytes.
OBJECTIVE
Benzoylaminoalkanohydroxamic acids, including 5-(4-dimethylaminobenzoyl)aminovaleric acid hydroxamide (4-Me(2)N-BAVAH), are structural analogues of Trichostatin A, a naturally occurring histone deacetylase inhibitor (HDACi). 4-Me(2)N-BAVAH has been shown to induce histone hyperacetylation and to inhibit proliferation in Friend erythroleukaemia cells in vitro. However, the molecular mechanisms have remained unidentified.


METHODS
In this study, we evaluated the effects of 4-Me(2)N-BAVAH on proliferation in non-malignant cells, namely epidermal growth factor-stimulated primary rat hepatocytes.


CONCLUSIONS
We have found that 4-Me(2)N-BAVAH inhibits HDAC activity at non-cytotoxic concentrations and prevents cells from responding to the mitogenic stimuli of epidermal growth factor. This results in an early G(1) cell cycle arrest that is independent of p21 activity, but instead can be attributed to inhibition of cyclin D1 transcription through a mechanism involving inhibition of nuclear factor-kappaB activation. In addition, 4-Me(2)N-BAVAH delays the onset of spontaneous apoptosis in primary rat hepatocyte cultures as evidenced by down-regulation of the pro-apoptotic proteins Bid and Bax, and inhibition of caspase-3 activation.
Papeleu
P
P
Department of Toxicology, Vrije Universiteit Brussel, Brussels, Belgium.
Wullaert
A
A
Elaut
G
G
Henkens
T
T
Vinken
M
M
Laus
G
G
Tourwé
D
D
Beyaert
R
R
Rogiers
V
V
Vanhaecke
T
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D017930:Genes, Reporter; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010421:Pentanoic Acids / Q000494:pharmacology*; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects
C521334:5-(4-dimethylaminobenzoyl)-aminovaleric acid hydroxamate; D056741:Cyclin D; D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; D010421:Pentanoic Acids; D008156:Luciferases