title: Histone deacetylase inhibitors induce differentiation of human endometrial adenocarcinoma cells through up-regulation of glycodelin.
abstract: Histone reversible acetylation, which is controlled by histone acetyltransferases and deacetylases, plays a fundamental role in gene transcription. Histone deacetylase inhibitors (HDACIs), such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have been characterized not only as anticancer drugs, but also as cytodifferentiation-inducing agents. In human endometrium, postovulatory production of progesterone directs estrogen-primed endometrial glandular cells to differentiate and thereby produce a number of unique bioactive substances, including glycodelin, that are critical for implantation at the secretory phase of the menstrual cycle. In this study, we show that TSA and SAHA, belonging to the hydroxamic acid group of HDACIs, can induce the phenotype of a human endometrial adenocarcinoma cell line, Ishikawa (originally derived from the glandular component of the endometrium), to differentiate to closely resemble normal endometrial epithelium in a time- and dose-dependent manner, as determined by morphological changes, synthesis of glycogen, and expression of secretory phase-specific proteins, including glycodelin. The proliferation- and differentiation-modulating effects elicited by TSA and SAHA at their optimal concentrations were comparable or more potent than those exerted by combined treatment with progesterone and estradiol. Furthermore, the gene silencing of glycodelin by small interference RNA resulted in the blockade of HDACI-induced differentiation in Ishikawa cells, suggesting the requirement for glycodelin for endometrial epithelial differentiation. Our results collectively indicate that TSA and SAHA are potent differentiation inducers for endometrial glandular cells, providing a clue for a possible therapeutic strategy to modulate endometrial function by targeting glycodelin.
authors.affiliation: Department of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchida
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Maruyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagashima
authors.forename: Hironori
authors.initials: H
authors.lastname: Asada
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Yoshimura
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D020868:Gene Silencing; D000071816:Glycodelin; D006003:Glycogen / Q000096:biosynthesis; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D053605:Leukemia Inhibitory Factor; D009994:Osmolar Concentration; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D011374:Progesterone / Q000008:administration & dosage / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D015854:Up-Regulation; D000077337:Vorinostat
chemical_list: D004791:Enzyme Inhibitors; D000071816:Glycodelin; D006023:Glycoproteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C045246:PAEP protein, human; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C012589:trichostatin A; D011374:Progesterone; D004958:Estradiol; D000077337:Vorinostat; D006003:Glycogen