Open AccessInhibition of NF‐κB activation by the histone deacetylase inhibitor 4‐Me 2 N‐BAVAH induces an early G 1 cell cycle arrest in primary hepatocytes
Author(s) -
Papeleu P.,
Wullaert A.,
Elaut G.,
Henkens T.,
Vinken M.,
Laus G.,
Tourwé D.,
Beyaert R.,
Rogiers V.,
Vanhaecke T.
Publication year - 2007
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/j.1365-2184.2007.00466.x
Subject(s) - trichostatin a , histone deacetylase , cyclin d1 , histone deacetylase inhibitor , apoptosis , cell cycle checkpoint , microbiology and biotechnology , cell cycle , cyclin b1 , cell growth , biology , histone deacetylase 5 , hdac11 , growth inhibition , chemistry , cancer research , histone , cyclin dependent kinase 1 , biochemistry , gene
. 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. Materials and 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. Results and Conclusion : 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.