title: Histone deacetylase inhibitors stimulate cell migration in human endometrial adenocarcinoma cells through up-regulation of glycodelin.
abstract: Histone deacetylase inhibitors (HDACIs) have recently emerged as promising anticancer drugs to induce cell cycle arrest, cytodifferentiation, and apoptosis. It is suggested, however, that HDACIs promote cell migration and invasion depending on the cell type. We have reported previously that treatment with HDACIs, including trichostatin A and suberoylanilide hydroxamic acid (SAHA) or progesterone in combination with estrogen, can induce cytodifferentiation of endometrial adenocarcinoma Ishikawa cells through up-regulation of glycodelin, a progesterone-induced endometrial glycoprotein. Given the reported role of glycodelin in cell motility and the migration-modulating potential of HDACIs, we investigated using wound healing assay and transwell migration assay whether ovarian steroid hormones, trichostatin A, or SAHA affects cell migration in endometrial cancer cell lines, Ishikawa and RL95-2. Treatment with ovarian steroid hormones, trichostatin A, and SAHA enhanced cell migration together with up-regulation of glycodelin. SAHA-augmented cell migration was almost completely blocked by gene silencing of glycodelin. Furthermore, overexpression of gycodelin alone resulted in increased cell motility in Ishikawa cells. Our results collectively indicate that glycodelin positively regulates cell motility acting as a mediator of HDACI-enhanced endometrial cell migration, suggesting the involvement of glycodelin in the dynamic endometrial gland morphogenesis during menstrual cycle. Our results raise a possibility that the use of HDACIs in the therapy for glycodelin-inducible endometrial and presumably other gynecological cancers may enhance invasion in cases in which the HDACIs fail to exert differentiation-inducing and/or antiproliferative effects.
authors.affiliation: Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchida
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Maruyama
authors.forename: Masanori
authors.initials: M
authors.lastname: Ono
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Ohta
authors.forename: Takashi
authors.initials: T
authors.lastname: Kajitani
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Masuda
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagashima
authors.forename: Toru
authors.initials: T
authors.lastname: Arase
authors.forename: Hironori
authors.initials: H
authors.lastname: Asada
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Yoshimura
mesh_terms: D000230:Adenocarcinoma / Q000503:physiopathology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D016889:Endometrial Neoplasms / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D000071816:Glycodelin; D006023:Glycoproteins / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D010053:Ovary / Q000378:metabolism; D011257:Pregnancy Proteins / Q000378:metabolism*; D015854:Up-Regulation; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005353:Fibronectins; D000071816:Glycodelin; D006023:Glycoproteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C045246:PAEP protein, human; D011257:Pregnancy Proteins; C012589:trichostatin A; D000077337:Vorinostat