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
Masaki Kitazono,
Rob Robey,
Zhirong Zhan,
Nicholas J. Sarlis,
Monica C. Skarulis,
Takashi Aikou,
Susan Bates and
Tito Fojo
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
beentried in an attempt to increase iodine uptake. We examined the
abilityof the novel histone deacetylase (HDAC) inhibitor, depsipeptide
(FR901228),to modulate the expression of thyroid-specific genes. Four
celllines, two derived from follicular thyroid carcinomas (FTC 133and
FTC 236) and two derived from anaplastic thyroid carcinomas(SW-1736
and KAT-4) were used. In these four cell lines, a verylow
concentration of depsipeptide (1 ng/mL) increased histoneacetylation
and expression of both thyroglobulin and the
Na+/I-symporter messenger RNAs. After 3 days,
messenger RNA levelsapproached those of a normal thyroid control.
Depsipeptide inducedincreases in 125I accumulation
indicated that a functional Na+/I-symporter
protein was induced. Transient transfections indicatethat the effects
are mediated at least in part by a trans-activating
factor.These in vitro results suggest that depsipeptide
or other histonedeacetylase inhibitors might be used clinically in
thyroid carcinomasthat are unable to trap iodine as an adjunct to
radioiodinetherapy.
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