The aim of this study was to comparatively investigate the effects of 5-azacytidine-C (5-Aza), trichostatin-A (TSA), and all-trans retinoic acid (ATRA) on the mRNA expressions of the sodium and iodine (Na/l) symporter (NIS), thyroglobulin (Tg), thyroid peroxidase (TPO), and the thyroid-stimulating hormone receptor (TSH-R), cis well as radioiodine (RAI) uptake in cancer (B-CPAP) and normal (Nthy-ori 3-1) thyroid cell lines. Cell lines were treated with 10 ng/mL of TSA, 5 mu M of 5-AZA, and I AM of ATRA, according to the MTT (methyl-thiazol-tetrazolium) test results. Additionally, recombinant thyroid-stimulating hormone (t-TSH) was also applied, with a selected dose of 100 ng/mL. Following the treatment, NIS, Tg, TPO, and TSH-R mRNA levels were detected by real-thne-polymerase chain reaction (RT-PCR) and RAI uptakes were measured by using a well counter as counts/cell number. 5-Aza increased TSH-R mRNA expression in both of the cell lines and decreased TPO, NIS, and Tg mRNA levels in the cancer cell line. In the normal thyroid cell line, 5-AZA increased TPO tnRNA levels by 2-old and made diffterences in NIS and Tg mRNA levels. TSA treatment repressed NIS and Tg mRNA levels and made no change on other thyroid-specific genes that were investigated in the cancer cell line. In the normal thyroid cell line, TSA increased TSH-R tnRNA levels in 72 hours and created no important difference in the other genes. ATRA repressed the TSH-R mRNA levels in the normal thyroid cell line and increased the TPO and Tg inRNA levels slightly in both the cell lines. Furthermore, in short-term, treatment, ATPA repressed the NIS gene expression slightly, but in the long term, this repression turned to basal levels. 5-Aza, TSA, and ATRA did not make any changes in RAI uptake in the cancer cell line, but rTSH increased RAI uptake significantly. In the normal thyroid cell line, TSA and ATRA decreased RAI uptake (to 1/10 and 112, respectively), but 5-Aza and rTSH increased RAI uptake significantly (2- and 4- Id, respectively). In our fio study, we showed an increase in TSH-R gene expression and radioiodine uptake with 5-Aza. Further in vitro and in vivo studies are needed to support our findings and the potential clinical use of this agent.