title: Trichostatin A specifically stimulates gonadotropin FSHβ gene expression in gonadotroph LβT2 cells.
abstract: Trichostatin A (TSA) is a selective inhibitor of mammalian histone deacetylase. In the present study, TSA was found to selectively increase gene expression of the pituitary gonadotropin β-subunit of follicle-stimulating hormone (FSH). Stimulation of mouse pituitary gonadotroph cell lines, LβT2, with TSA for 24 h resulted in no change in mRNA expression of the α- and LHβ-subunit. On the other hand, FSHβ-subunit mRNA expression was significantly increased in a dose-dependent fashion. Similarly, specific induction of the FSHβ-subunit gene with TSA stimulation was observed in primary cultures of rat pituitary cells. Histone acetylation in whole cell lysates of LβT2 cells was significantly increased after TSA treatment, but not gonadotropin-releasing hormone (GnRH) treatment. The effect of TSA on FSHβ mRNA expression was prominent compared to that of GnRH; however, TSA-stimulated FSHβ mRNA expression was significantly reduced with combined TSA and GnRH treatment. TSA caused a slight increase in extracellular signal-regulated kinase (ERK) phosphorylation, while GnRH-increased ERK phosphorylation was potentiated in the presence of TSA. In addition, TSA, but not GnRH, significantly stimulated gene expression of retinaldehyde dehydrogenase 1 (RALDH1), a retinoic acid (RA) synthesizing enzyme involved in cell differentiation. These findings demonstrate that TSA specifically increases FSHβ subunit gene expression with a concomitant increase in whole cell histone acetylation. Moreover, although GnRH is a stimulator of FSHβ gene expression, it interfered with the stimulatory effect of TSA on FSHβ mRNA expression, without modification of TSA-increased whole cell histone acetylation. This suggests that the mechanisms of TSA and GnRH-induced gonadotropin subunit gene expression are entirely distinct.
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Oride
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Kanasaki
authors.forename: Tselmeg
authors.initials: T
authors.lastname: Mijiddorj
authors.forename: Unurjargal
authors.initials: U
authors.lastname: Sukhbaatar
authors.forename: Kohji
authors.initials: K
authors.lastname: Miyazaki
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D037201:Follicle Stimulating Hormone, beta Subunit / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D052681:Gonadotrophs / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D050697:Retinal Dehydrogenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D037201:Follicle Stimulating Hormone, beta Subunit; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007527:Isoenzymes; D007987:Gonadotropin-Releasing Hormone; C012589:trichostatin A; D000080924:Aldehyde Dehydrogenase 1 Family; C515028:ALDH1A1 protein, mouse; C523119:Aldh1a1 protein, rat; D050697:Retinal Dehydrogenase