Endocrine Abstracts (2004) 7 P81

Deacetylating agents as mediators of iodide uptake and efflux in thyroid and breast

C Clarke, E Burbridge & PPA Smyth

Endocrine Laboratory, Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Ireland.

Epigenetic phenomena such as methylation or acetylation of DNA can result in transcriptional inactivation and gene silencing. In the thyroid such phenomena can bring about the loss of ability to accumulate iodide as a result of methylation of CpG islands in human sodium iodide symporter (NIS) and Pendrin (PDS) DNA, limiting the ability to utilise radioiodide therapy. This study examines the effects of Trichostatin A (TSA) a histone deacetylase (HDAC) inhibitor on a rat thyroid cell line FRTL-5, and the human breast cancer cell line MCF-7. HDAC inhibitors prevent the removal of acetyl groups from the histone tail of NIS DNA, interfering with methylation, enhancing or reversing transcription. NIS and PDS expression were determined by semiquantitative RT-PCR as a ratio to the housekeeper gene GAPDH. Cells were incubated with TSA for 72 hours, 125I added and incubation continued for another 4 hours. In FRTL-5 cells, uptake and efflux was diminished in a concentration dependent manner. NIS expression relative to GAPDH remained constant at all TSA concentrations, whereas PDS expression decreased as TSA concentrations increased. 125I uptake and efflux in MCF-7 cells showed a decrease at all concentrations of TSA with a concentration dependent decrease in NIS expression. In addition the presence of TSA decreased rPDS and hNIS transcription. While demethylating agents produce an increase in 125I uptake by cell lines, the histone deacetylase inhibitor TSA has an opposite effect. It is evident that interpretation of the effects of demethylating and deacetylation must be treated with caution. It may be that prior demethylation of histone groups within DNA is required in order to produce optimised effects of deacetylation (TSA) treatment. At present the greatest potential for TSA in iodide transport is its ability to reduce efflux of administered radioactive iodide and thus by promoting retention increase its ablative capacity.

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