The novel histone deacetylase inhibitor 4-Me2N-BAVAH differentially affects cell junctions between primary hepatocytes.
Histone deacetylase (HDAC) inhibitors show great pharmaceutical potential, particularly in relation to cancer. However, very little is known about their biological outcome on hepatocytes, the major executors of xenobiotic biotransformation in the organism. The current study was set up to investigate the effects of the newly synthesized HDAC inhibitor 5-(4-dimethylaminobenzoyl)-aminovaleric acid hydroxamate (4-Me(2)N-BAVAH) on hepatocyte gap junctions and adherens junctions, being main guardians of liver homeostasis. For that purpose, freshly isolated rat hepatocytes were cultivated for 7 days either in the absence or presence of 50 microM 4-Me(2)N-BAVAH. Gap junction activity became promoted upon exposure to 4-Me(2)N-BAVAH, which was associated with elevated Cx32 protein levels. By contrast, both Cx26 and Cx43 protein levels were negatively affected. The modifications in connexin protein content were not reflected at the transcriptional level. Finally, neither the expressions nor the cellular localizations of the adherens junction building stones E-cadherin, beta-catenin and gamma-catenin were altered by 4-Me(2)N-BAVAH, a finding that is in contrast to what is commonly observed in tumor cells following exposure to HDAC inhibitors.
Vinken
Mathieu
M
Department of Toxicology, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. mvinken@vub.ac.be
Henkens
Tom
T
Snykers
Sarah
S
Lukaszuk
Aneta
A
Tourwé
Dirk
D
Rogiers
Vera
V
Vanhaecke
Tamara
T
D000107:Acetylation / Q000187:drug effects; D022005:Adherens Junctions / Q000187:drug effects*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000072259:Connexin 26; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D010421:Pentanoic Acids / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000097002:Gap Junction beta-1 Protein
D000072259:Connexin 26; D018031:Connexin 43; D017630:Connexins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D010421:Pentanoic Acids; D000097002:Gap Junction beta-1 Protein; C521334:5-(4-dimethylaminobenzoyl)-aminovaleric acid hydroxamate; C000607044:Gjb2 protein, rat