B-RafV600E inhibits sodium iodide symporter expression via regulation of DNA methyltransferase 1

B-RafV600E mutant is found in 40–70% of papillary thyroid carcinoma (PTC) and has an important role in the pathogenesis of PTC. The sodium iodide symporter (NIS) is an integral plasma membrane glycoprotein that mediates active iodide transport into the thyroid follicular cells, and B-RafV600E has been known to be associated with the loss of NIS expression. In this study, we found that B-RafV600E inhibited NIS expression by the upregulation of its promoter methylation, and that specific regions of CpG islands of NIS promoter in B-RafV600E harboring PTC were highly methylated compared with surrounding normal tissue. Although DNA methyltransferase 3a and 3b (DNMT3a,3b) were not increased by B-RafV600E, DNMT1 expression was markedly upregulated in PTC and B-RafV600E expressing thyrocytes. Furthermore, DNMT1 expression was upregulated by B-RafV600E induced NF-κB activation. These results led us to conclude that NIS promoter methylation, which was induced by B-RafV600E, is one of the possible mechanisms involved in NIS downregulation in PTC. A mutation associated with thyroid cancer thwarts treatment by actively inhibiting the uptake of a commonly used therapeutic agent. The thyroid absorbs iodine via specialized transport proteins, and radioactive iodine can efficiently kill thyroid tumors. Many thyroid cancers have a specific mutation in a particular signaling pathway. Researchers led by Tae Jun Park and Jang Hee Kim at Ajou University in South Korea have now shown how this mutation helps some tumors elude destruction by inhibiting the production of sodium-iodide symporter (NIS), a critical iodine-transporting protein. The mutation initiates a chain of events that cause cancer cells to produce an enzyme that inactivates the gene encoding NIS. This results in reduced uptake of iodine, resulting in tumors that are harder to destroy and thus more likely to prove lethal.