Effects of histone deacetylase inhibitors on estradiol-induced proliferation and hyperplasia formation in the mouse uterus.
It is suggested that estrogen hormones recruit mechanisms controlling histone acetylation to bring about their effects in the uterus. However, it is not known how the level of histone acetylation affects estrogen-dependent processes in the uterus, especially proliferation and morphogenetic changes. Therefore, this study examined the effects of histone deacetylase blockers, trichostatin A and sodium butyrate, on proliferative and morphogenetic reactions in the uterus under long-term estrogen treatment. Ovari-ectomized mice were treated with estradiol dipropionate (4 microg per 100 g; s.c., once a week) or vehicle and trichostatin A (0.008 mg per 100 g; s.c., once a day) or sodium butyrate (1% in drinking water), or with no additional treatments for a month. In animals treated with estradiol and trichostatin A or sodium butyrate, uterine mass was increased, and abnormal uterine glands and atypical endometrial hyperplasia were found more often. Both histone deacetylase inhibitors produced an increase in the numbers of mitotic and bromodeoxyuridine-labelled cells in luminal and glandular epithelia, in stromal and myometrial cells. Levels of estrogen receptor-alpha and progesterone receptors in uterine epithelia, stromal and myometrial cells were decreased in mice treated with estradiol and trichostatin A or sodium butyrate. Expression of beta-catenin in luminal and glandular epithelia was attenuated in mice treated with estradiol with trichostatin A or sodium butyrate. Both histone deacetylase inhibitors have similar unilateral effects; however the action of trichostatin A was more expressed than that of sodium butyrate. Thus, histone deacetylase inhibitors exert proliferative and morphogenetic effects of estradiol. The effects of trichostatin A and sodium butyrate are associated with changes in expression of estrogen receptor-alpha, progesterone receptors and beta-catenin in the uterus.
Gunin
Andrei G
AG
Department of Obstetrics and Gynecology, Medical School Chuvash State University, PO Box 86, 428034, Cheboksary, Russia. drgunin@myrealbox.com
Kapitova
Irina N
IN
Suslonova
Nina V
NV
D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000032:analysis; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000032:analysis; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology*; D006965:Hyperplasia; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D011980:Receptors, Progesterone / Q000032:analysis; D015534:Trans-Activators / Q000032:analysis; D014599:Uterus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051176:beta Catenin
D002087:Butyrates; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D047628:Estrogen Receptor alpha; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011980:Receptors, Progesterone; D015534:Trans-Activators; D051176:beta Catenin; C012589:trichostatin A; D004958:Estradiol