Inhibitory effects of trichostatin A on adrenocorticotropic hormone production and proliferation of corticotroph tumor AtT-20 cells.
Cushing's disease is primarily caused by adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. Pituitary tumor-transforming gene 1 (PTTG1) expression, a hallmark of pituitary tumors, stimulates pituitary cell proliferation. Histone deacetylases (HDACs) play an important role in regulating gene transcription and HDAC inhibitors induce cellular differentiation and suppress tumor cell proliferation. HDAC inhibitors also repress PTTG1 mRNA levels. Trichostatin A (TSA) is a potent cell-permeable HDAC inhibitor that blocks cell cycle progression. In the present study, we determined the effect of TSA on ACTH production and cellular proliferation in mouse AtT-20 corticotroph tumor cells. TSA decreased proopiomelanocortin (POMC) mRNA levels in AtT-20 cells and reduced ACTH levels in the culture medium of these cells. The TSA-induced decreases in POMC mRNA levels were not modulated when TSA and dexamethasone were simultaneously administered. Drug treatment also decreased AtT-20 cell proliferation, induced apoptosis, and increased the percentage of cells in G0/G1 phase using flow cytometry. TSA decreased PTTG1 mRNA levels. Furthermore, PTTG1 knockdown inhibited cellular proliferation. Its knockdown also inhibited POMC mRNA and ACTH levels. TSA inhibits ACTH production and corticotroph tumor cell proliferation. TSA may inhibit cellular proliferation, and ACTH synthesis and secretion by decreasing PTTG1 expression.
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Aomori 036-8562, Japan.
Yuki
Y
Nakada
Kazunori
K
Kageyama
Aya
A
Sugiyama
Rie
R
Desaki
Shinobu
S
Takayasu
Kanako
K
Niioka
Shingo
S
Murasawa
Noriko
N
Ishigame
Yuko
Y
Asari
Yasumasa
Y
Iwasaki
Makoto
M
Daimon
D049913:ACTH-Secreting Pituitary Adenoma / Q000378:metabolism* / Q000473:pathology*; D000324:Adrenocorticotropic Hormone / Q000032:analysis / Q000096:biosynthesis*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D047748:Pituitary ACTH Hypersecretion; D011333:Pro-Opiomelanocortin / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D064249:Securin / Q000235:genetics
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human; C012589:trichostatin A; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone