Abstract Background: About 10∼20% of thyroid cancer patients does not respond to radioactive iodine(RAI) therapy, since the expression or membrane trafficking of sodium iodine symporter(NIS) was ameliorated. We investigated whether iodine uptake and expression of NIS were regulated by the balance of SUMOylation in thyroid cancer. Methods: We analyzed the expression of NIS mRNA using fresh frozen tissues of papillary thyroid cancer. After overexpression of desumoylating enzyme SENP2 in human anaplastic thyroid cancer cell line (FRO) and silencing SENP2 in human NIS-overexpressed HeLa cell line (HeLa-hNIS), we evaluated the expression of NIS mRNA and iodine uptake. We selected 30 patients of different expression level of SENP2 (low and normal SENP2) and constructed tissue microarray for immunohistochemistry stain. And the patients’ clinico-pathologic features were reviewed using medical records. Results: Twenty six percent of papillary thyroid cancer tissue showed reduced expression of SENP2 and NIS mRNA. Silencing SENP2 in HeLa-hNIS, NIS mRNA and iodine uptake was reduced. By co-immunoprecipitation, the interaction between SUMO2/3 and C/EBPβ was detected. After overexpression of SENP2, NIS mRNA and iodine uptake was restored. By comparison of response of RAI among two groups, reduction of serum thyroglobulin level after RAI was blunted in the group of low SENP2, compared to that in the group of normal SENP2. Conclusion: Overexpression of SENP2 can induce NIS expression and iodine uptake. This may be a novel therapeutic target for RAI-refractory thyroid cancer patients. Citation Format: Eun Kyung Lee, Min Ji Park, You Jin Lee. Regulation of iodine uptake by SENP2 in thyroid cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3466. doi:10.1158/1538-7445.AM2015-3466