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.
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea.
Yong Won
YW
Choi
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea.
Hyun-Ju
HJ
Kim
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea.
Young Hwa
YH
Kim
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea.
So Hyun
SH
Park
Department of Microbiology, Ajou University School of Medicine, Suwon, Korea.
Yong Jun
YJ
Chwae
Department of Surgery, Ajou University School of Medicine, Suwon, Korea.
Jeonghun
J
Lee
Department of Surgery, Ajou University School of Medicine, Suwon, Korea.
Euy Young
EY
Soh
Department of Pathology, Ajou University School of Medicine, Suwon, Korea.
Jang-Hee
JH
Kim
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea.
Tae Jun
TJ
Park
D001483:Base Sequence; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D027981:Symporters / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D000099209:Sodium-Iodide Symporters
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D048493:Proto-Oncogene Proteins B-raf; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C000717967:DNMT3A protein, human; C000619380:DNMT1 protein, human