Human sodium-iodide symporter (hNIS) gene expression is inhibited by a trans-active transcriptional repressor, NIS-repressor, containing PARP-1 in thyroid cancer cells

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18 Scopus citations

Abstract

Radioiodine remains the only tumoricidal therapy for disseminated thyroid carcinomas; however, dedifferentiated tumors lose the expression of human sodium-iodide symporter (hNIS) gene, and cannot respond to this treatment. Previous studies suggested that a trans-active protein factor (NIS-repressor) represses endogenous hNIS transcription, likely contributing to the loss of radioiodine uptake, and defined the NIS-repressor binding site (NRBS) in the proximal hNIS promoter. Using electrophoretic mobility shift assay (EMSA), we found evidence of NIS-repressor in the nuclear extract from KAK-1 cells, and confirmed this result using nuclear extracts prepared from multiple verified thyroid cell lines. Luciferase reporter assays of hNIS promoter constructs and EMSA were used to define two core sequences, NRBS-P and NRBS-D, in the hNIS promoter as the binding sites for NIS-repressor. Electrophoretic analysis of KAK-1 nuclear extract proteins cross-linked with NRBS-P suggests that NIS-repressor is a protein complex. Analysis of KAK-1 nuclear extract proteins bound to NRBS-P, via liquid chromatography coupled with tandem mass spectroscopy, demonstrated poly(ADP-ribose) polymerase-1 (PARP-1) as a NIS-repressor component. Pharmacological inhibition of PARP-1 enzymatic activity using PJ34 stimulated both the luciferase reporter activity driven by hNIS promoter and the endogenous hNIS mRNA level. Supershift studies suggest that thyroid transcription factor 2 (TTF-2) is also associated with the NIS-repressor complex. NIS-repressor, including its PARP-1 component, presents a potential therapeutic target to restore radioiodine uptake in dedifferentiated thyroid carcinomas.

Original languageEnglish
Pages (from-to)383-398
Number of pages16
JournalEndocrine-Related Cancer
Volume17
Issue number2
DOIs
StatePublished - Jun 2010

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

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