Histone acetylation and steroid receptor coactivator expression during clofibrate-induced rat hepatocarcinogenesis.
Peroxisome proliferators (PPs), non-genotoxic rodent carcinogens, cause the induction of the peroxisomal fatty acid beta-oxidation system, including bifunctional enzyme (BE) and 3-ketoacyl-CoA thiolase (TH), in the liver. GST M1 gene is polymorphic in Sprague-Dawley rats, NC- and KS-type. The KS-type rats showed enhanced susceptibility to ethyl-alpha-chlorophenoxyisobutyrate (clofibrate, CF), one of the PPs. The degree of BE induction was higher in the KS-type and preneoplastic foci developed after 6-8 weeks of treatment, whereas no foci developed in the NC-type. In the preset study, factors involved in different BE inducibility were investigated. There were no differences in hepatic peroxisome proliferator-activated receptor (PPAR) alpha levels between them. Among various coactivators for PPARalpha, only steroid receptor coactivator (SRC)-3 level was higher in the KS-type. To investigate the association between PPARalpha and SRC-3 or other proteins, nuclear extracts from CF-treated livers were applied to a PPARalpha column. In the KS-type, 110, 72, and 42 kDa proteins were bound and these were identified as SRC-3, BE, and TH, respectively. EMSA supported the binding of these proteins to PPARalpha associated to the BE enhancer in CF-treated KS-type, but not in the NC-type. Histone H3 acetylation was increased 11-fold in the KS-type by CF treatment but not in the NC-type. As BE and TH are responsible for acetyl-CoA production and SRC-3 possesses a histone acetyltransferase activity, these results suggest that enhanced BE induction in the KS-type livers is due to acetylation-mediated transcriptional activation and epigenetic mechanisms might be involved in CF-induced rat hepatocarcinogenesis.
Asano
Jumpei
J
Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Kudo
Toshihiro
T
Shimizu
Takeshi
T
Fan
Yang
Y
Nanashima
Naoki
N
Yamana
Daisuke
D
Miura
Takuya
T
Yamada
Toshiyuki
T
Tsuchida
Shigeki
S
D000105:Acetyl Coenzyme A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002994:Clofibrate; D004790:Enzyme Induction; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D020025:Peroxisome Proliferators / Q000378:metabolism / Q000494:pharmacology; D011110:Polymorphism, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism
D005227:Fatty Acids; D006657:Histones; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011987:Receptors, Steroid; D000105:Acetyl Coenzyme A; D056921:Nuclear Receptor Coactivator 3; D000101:Acetyl-CoA C-Acetyltransferase; D002994:Clofibrate