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Effects of Histone Deacetylase Inhibitors on Estradiol-Induced Proliferation and Hyperplasia Formation in the Mouse Uterus

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Effects of Histone Deacetylase Inhibitors on Estradiol-Induced Proliferation and Hyperplasia Formation in the Mouse Uterus 539 Effects of histone deacetylase inhibitors on estradiol-induced proliferation and hyperplasia formation in the mouse uterus Andrei G Gunin, Irina N Kapitova and Nina V Suslonova Department of Obstetrics and Gynecology, Medical School Chuvash State University, PO Box 86, 428034, Cheboksary, Russia (Requests for offprints should be addressed to A G Gunin; Email: [email protected]) Abstract It is suggested that estrogen hormones recruit mechanisms of mitotic and bromodeoxyuridine-labelled cells in luminal controlling histone acetylation to bring about their effects and glandular epithelia, in stromal and myometrial cells. in the uterus. However, it is not known how the level of Levels of estrogen receptor- and progesterone receptors histone acetylation affects estrogen-dependent processes in in uterine epithelia, stromal and myometrial cells were the uterus, especially proliferation and morphogenetic decreased in mice treated with estradiol and trichostatin A changes. Therefore, this study examined the effects of or sodium butyrate. Expression of -catenin in luminal histone deacetylase blockers, trichostatin A and sodium and glandular epithelia was attenuated in mice treated butyrate, on proliferative and morphogenetic reactions in with estradiol with trichostatin A or sodium butyrate. Both the uterus under long-term estrogen treatment. Ovari- histone deacetylase inhibitors have similar unilateral effects; ectomized mice were treated with estradiol dipropionate however the action of trichostatin A was more expressed (4 µg per 100 g; s.c., once a week) or vehicle and tricho- than that of sodium butyrate. Thus, histone deacetylase statin A (0·008 mg per 100 g; s.c., once a day) or sodium inhibitors exert proliferative and morphogenetic effects of butyrate (1% in drinking water), or with no additional estradiol. The effects of trichostatin A and sodium butyrate treatments for a month. In animals treated with estradiol are associated with changes in expression of estrogen and trichostatin A or sodium butyrate, uterine mass was receptor-, progesterone receptors and -catenin in the increased, and abnormal uterine glands and atypical endo- uterus. metrial hyperplasia were found more often. Both histone Journal of Endocrinology (2005) 185, 539–549 deacetylase inhibitors produced an increase in the numbers Introduction factors and others (Couse & Korach 1999, Gunin et al. 2001). Recent data showed that estrogen also recruits Estrogen hormones have a variety of effects in the uterus. intracellular regulatory systems to bring about its action Proliferation and changes in structure and architecture of (Couse & Korach 1999, Deroo et al. 2004, Gunin et al. uterine tissues are estrogen-dependent events (Martin et al. 2004b). The scientific literature gives some direct and 1973, Bigsby 2002). Endometrial cancer is also an estrogen- indirect evidence that the system that maintains the status dependent disease, and it can be regarded as a consequence of histone acetylation interacts with estrogen signalling of estrogen-induced alteration in proliferation and mor- (Alao et al. 2004, Kurtev et al. 2004, Margueron et al. phogenesis (Emons et al. 2000, Archer 2004). Endometrial 2004). hyperplasia and cancer can easily be induced in laboratory Several types of histone deacetylases are present in the rodents by continuous estrogen exposure (Akhmedkhanov nucleus of cells, and together with histone acetyltrans- et al. 2001). Administration of estrogen hormones can lead ferases they determine the acetylation status of histone to endometrial cancer formation in women (Deligdisch proteins (Margueron et al. 2004). Shifts in the level of 2000). Numerous cases of endometrial cancer are regis- histone acetylation are accompanied by changes in the tered each year in every country (Archer 2004). Therefore, activity of the transcription process (Riester et al. 2004). regulation of estrogen action and the interactions between Histone deacetylase activity keeps chromatin in a tran- estrogens and target tissues must be investigated more scriptionally inactive state (Riester et al. 2004). Data have intensively in order to achieve more effective prevention been published showing interactions between estrogen and treatment of estrogen-dependent pathology. signalling and acetylation of histones (Jang et al. 2004, It is known that the action of estrogen is regulated by a Margueron et al. 2004). It has also been reported that variety of extracellular factors – such as hormones, growth estrogen hormones affect the level of histone acetylation in Journal of Endocrinology (2005) 185, 539–549 DOI: 10.1677/joe.1.06118 0022–0795/05/0185–539 2005 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/29/2021 11:59:44PM via free access 540 A G GUNIN and others · Histone deacetylase and estradiol action in the uterus target tissues (Sun et al. 2001). There is some evidence that allowed to drink tap water with 1% (w/v) sodium butyrate histone acetylation is involved in processes that are also (Sigma) for 30 days. These groups also received s.c. regulated by estrogens, for example proliferation and cell injections of saline (0·1 ml per mouse) once a day for differentiation (Sakai et al. 2003). It is therefore supposed 30 days. that shifts in histone acetylation can affect the action of The fourth (n=5), fifth (n=5) and sixth (n=5) groups estrogen on the uterus, such as proliferation and morpho- received s.c. injections of the vehicle of estradiol (olive oil; genetic alterations. However, it is not known how the 0·1 ml per mouse) once a week and saline or trichostatin A histone acetylation status influences estrogen-dependent or sodium butyrate, respectively, once a day for 30 days. processes in the uterus, such as proliferation and changes in Our previous observations clearly showed that treat- structure of tissues. Therefore, the aim of this research ment with estradiol for 30 days was quite enough to was to examine estrogen-induced processes in the uterus produce expressed estrogen-dependent changes in uterine and their response to substances that change the level of morphology and to induce hyperplastic changes in the histone acetylation. uterus (Gunin et al. 2001, 2002, 2004a,b). This estradiol Trichostatin A, an antifungal antibiotic, has a potent and dose and treatment regime produced estradiol levels in the specific inhibitory effect on histone deacetylase activity blood that were close to the normal physiologic values (Riester et al. 2004). Butyric acid and its salts are also (Gunin et al. 2004a). well-known blockers of the activity of histone deacetylases The uteri were removed 48 h after the last estradiol or (Riester et al. 2004). Therefore two reagents, trichostatin vehicle injection. All animals were injected i.p. with A and sodium butyrate, were chosen for use in our bromodeoxyuridine (BrdU; 5 mg per 100 g of body mass; experiments to block histone deacetylases; this was fol- Sigma) dissolved in 0·15 M sodium chloride 2 h before the lowed by induction of a hyperacetylated histone state. tissues were removed. Organs were removed under deep ether anesthesia. Uteri were weighed and middle seg- ments of uterine horns were then placed in modified Material and Methods Bouin’s fixative (Gunin et al. 2000) for 6 h at room temperature, and were then dehydrated and embedded Animals in paraffin. Uteri were transversely oriented and cut at 5–7 µm. All procedures were performed in accordance with the UFAW Handbook on the Care and Management of Laboratory Animals and with the Chuvash State Univer- Uterine histology sity Rules for work with laboratory animals. White out- Histological changes in the uterus were analyzed and bred CFW female mice (19·1 0·3 g, mean S.E.M.) diagnosed according to Scully et al. (1994). To estimate were used. Animals were obtained from the Animal the extent of any hyperplastic or neoplastic changes in the Department of Chuvash State University (Cheboksary, endometrium, uterine glands were subdivided into four Russia) and were housed with free access to water and morphological types: (1) normal glands (simple tubular food. Mice were ovariectomized 2 weeks before the glands which can appear in section as round, oval, or experiments were started. All surgical procedures were elongated with a narrow lumen; this type has no branches performed under anesthesia with ketamine and diazepam or daughter glands); (2) cystic glands (round-shaped glands (75 and 0·12 mg/kg respectively, i.p.; Gedeon-Richter, of more than average or large size); (3) glands with Budapest, Hungary). daughter glands (these glands have various shapes (round, elongate, tortuous) and sizes and have forming or formed daughter gland or glands inside the epithelium or inside Treatments the mother gland lumen, or on the outer surface of the Ovariectomized mice were divided into several groups mother gland); (4) conglomerate of glands (this type has a according to the treatments, as follows. The first group very complex architecture in which individual glands are (n=15) was treated with s.c. injections of estradiol dipro- closely disposed to each other almost without intervening pionate in olive oil (Minmedprom, Rostov-Don, Russia) stroma and have multiple interconnecting lumens – this at a dose of 4 µg per 100 g of body mass once a week and type may develop from glands with daughter glands), as received s.c. injections of saline (0·15 M sodium chloride) described in Gunin et al. 2001). The numbers of each type at a dose of 0·1 ml per mouse once a day for 30 days. The of gland were calculated in randomly selected sections. No second group (n=15) was treated with s.c. injections of less than three sections from each animal were examined. estradiol once a week and received s.c. injections of Results were expressed as the percentage of each type of trichostatin A (Sigma) at a dose 0·008 mg per 100 g once gland. The epithelium of all glands in randomly selected a day for 30 days.
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