Hypermethylation of a New Distal Sodium/Iodide Symporter (NIS) Enhancer (NDE) Is Associated With Reduced NIS Expression in Thyroid Tumors

Hypermethylation of a New Distal Sodium/Iodide Symporter (NIS) Enhancer (NDE) Is Associated With Reduced NIS Expression in Thyroid Tumors

Author Galrao, Ana Luiza Google Scholar
Camargo, Rosalinda Y. Google Scholar
Friguglietti, Celso U. Google Scholar
Moraes, Lais Autor UNIFESP Google Scholar
Cerutti, Janete Maria Autor UNIFESP Google Scholar
Serrano-Nascimento, Caroline Google Scholar
Suzuki, Miriam F. Google Scholar
Medeiros-Neto, Geraldo Google Scholar
Rubio, Ileana Gabriela Sanchez de Autor UNIFESP Google Scholar
Institution Universidade de São Paulo (USP)
Head & Neck Surg Santa Catarina Hosp
Universidade Federal de São Paulo (UNIFESP)
Abstract Context: in thyroid tumors, reduced radioiodine uptake is associated with worse patient outcome concomitantly with low sodium/iodide symporter (NIS) mRNA expression. Previous studies showed that CpG-island methylation in the NIS proximal promoter does not correlate with mRNA expression.Objectives: the aim of the study was to identify new CpG-islands within the NIS 5' region and investigate the involvement of their methylation in NIS expression.Design: DNA was obtained from 30 pairs of thyroid samples: tumor (T) and surrounding nontumor (NT) samples. All T samples had reduced NIS mRNA expression compared to NT samples.Main Outcome Measures: Methylation degree was quantified by bisulfite sequencing, and NIS expression by real-time PCR and Western blot. Reporter gene assays were performed to determine CpG-island functionality. Tumor cell cultures were treated with 5-Aza demethylating agent to determine NIS expression, methylation status, and I-125 uptake.Results: We identified a new CpG-island2 with 14 CpG sites, located -2152/-1887 relative to ATG site. CpG-island2 was hypermethylated in T compared to NT samples, in both benign and malignant tumor groups. There was a significant inverse correlation between NIS mRNA expression and degree of CpG-island2 methylation in NT and T samples. This sequence increased the expression of a reporter gene; thus, it was considered a new enhancer. Cell culture treatments with 5-Aza reduced CpG-island2 methylation levels concomitantly with restoration of NIS mRNA and protein expression and I-125 uptake.Conclusions: We identified a new distal enhancer, NIS distal enhancer, that regulates gene expression through DNA methylation. This enhancer is hypermethylated in T compared to NT samples and is associated with decreased NIS expression in tumors. This epigenetic deregulation may be an early event in tumorigenesis.
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Instituto da Tiroide, São Paulo, Brazil
Grant number FAPESP: 2007/51235-7
FAPESP: 2007/51236-3
FAPESP: 2009/52517-1
Date 2014-06-01
Published in Journal of Clinical Endocrinology & Metabolism. Washington: Endocrine Soc, v. 99, n. 6, p. E944-E952, 2014.
ISSN 0021-972X (Sherpa/Romeo, impact factor)
Publisher Endocrine Soc
Extent E944-E952
Origin http://dx.doi.org/10.1210/jc.2013-1450
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000342340500002
URI http://repositorio.unifesp.br/handle/11600/37804

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