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Low Concentrations of the Histone Deacetylase Inhibitor, Depsipeptide (FR901228), Increase Expression of the Na⁺/I^- Symporter and Iodine Accumulation in Poorly Differentiated Thyroid Carcinoma Cells

Medicine Branch (M.K., R.R., Z.Z., S.B., T.F.), DCS, National Cancer Institute, Bethesda, Maryland 20892; Clinical Endocrinology Branch (N.S., M.C.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and First Department of Surgery (T.A.), Faculty of Medicine, Kagoshima University, Sakuragaoka, Kagoshima 890-8520, Japan

Address all correspondence and requests for reprints to: Tito Fojo, M.D., Building 10, NCI, NIH, Room 12N226, 9000 Rockville Pike, Bethesda, Maryland 20892. E-mail: tfojo{at}helix.nih.gov

Abstract

Thyroid carcinoma accounts for the majority of deaths from endocrine cancers. A major cause of treatment failure is the inability to trap iodine. Chemotherapeutic agents with differentiating properties have been tried in an attempt to increase iodine uptake. We examined the ability of the novel histone deacetylase (HDAC) inhibitor, depsipeptide (FR901228), to modulate the expression of thyroid-specific genes. Four cell lines, two derived from follicular thyroid carcinomas (FTC 133 and FTC 236) and two derived from anaplastic thyroid carcinomas (SW-1736 and KAT-4) were used. In these four cell lines, a very low concentration of depsipeptide (1 ng/mL) increased histone acetylation and expression of both thyroglobulin and the Na⁺/I^- symporter messenger RNAs. After 3 days, messenger RNA levels approached those of a normal thyroid control. Depsipeptide induced increases in ¹²⁵I accumulation indicated that a functional Na⁺/I^- symporter protein was induced. Transient transfections indicate that the effects are mediated at least in part by a trans-activating factor. These in vitro results suggest that depsipeptide or other histone deacetylase inhibitors might be used clinically in thyroid carcinomas that are unable to trap iodine as an adjunct to radioiodine therapy.

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