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

Abstract

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.

LncRNA LUCAT1 as a novel prognostic biomarker for patients with papillary thyroid cancer

“…Both histone deacetylation (supported by HDACs) 41 and DNA methylation (by DNA methyl transferases, DNMTs) 42 are two relevant gene-silencing mechanisms which accelerate the progression of many cancers. DNMT1 and HDAC1 are known to be upregulated in PTC 43,44 .…”

NADPH Oxidase NOX4 Is a Critical Mediator of BRAFV600E-Induced Downregulation of the Sodium/Iodide Symporter in Papillary Thyroid Carcinomas

“…This mechanism could involve redox-sensitive epigenetic modifications, such as DNA methylation and histone acetylation (18). Hypermethylation of the NIS promoter is observed in BRAF V600E harboring PTC (10,42), and the use of demethylating agents has been shown to restore decreased iodine uptake to cells with methylated promoter regions in vivo. ROS have been shown to provide an oxidative stressmediated epigenetic imbalance, which perturbed genomic integrity in numerous oxygen radical-induced injuries, disturbing the DNA demethylation mechanisms (33).…”

“…A clinical study using the MAPK inhibitor selumetinib to reverse refractoriness to radioiodine in patients with radioiodine refractory metastatic thyroid cancer partially restored radioactive iodine (RAI) incorporation in patients with BRAF-mutated tumors, but yielded much better results in patients with RAS-mutated tumors (10). Analysis of human PTC (TCGA) shows that the NOX4 expression level is correlated to ERK activation.…”

Targeting the BRAF Signaling Pathway in CD133pos Cancer Stem Cells of Anaplastic Thyroid Carcinoma

“…BRAF (B-Rapidly Accelerated Fibroblast) as a serine/threonine-protein kinase, is a member of the mitogen-activated protein kinase (MAPK) pathway. Its gene mutations, like BRAF V600E , with different ways, such as the intensive activation of TGFβ/Smad signaling, histone deacetylation of NIS promoter, and the regulation of DNA methyl transferase 1, can be effected on the NIS gene expression and function (Bozorg-Ghalati et al, 2016;Choi et al, 2014;Zhang et al, 2014;Riesco-Eizaguirre et al, 2009).…”