Abstract
Thyroid iodide accumulation via the sodium/iodide symporter (NIS; SLC5A5) has been the basis for the longtime use of radio-iodide in the diagnosis and treatment of thyroid cancers. NIS is also expressed, but poorly functional, in some non-thyroid human cancers. In particular, it is much more strongly expressed in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) cell lines than in primary human hepatocytes (PHH). The transcription factors and signaling pathways that control NIS overexpression in these cancers is largely unknown. We identified two putative regulatory clusters of p53-responsive elements (p53REs) in the NIS core promoter, and investigated the regulation of NIS transcription by p53-family members in liver cancer cells. NIS promoter activity and endogenous NIS mRNA expression are stimulated by exogenously expressed p53-family members and significantly reduced by member-specific siRNAs. Chromatin immunoprecipitation analysis shows that the p53–REs clusters in the NIS promoter are differentially occupied by the p53-family members to regulate basal and DNA damage-induced NIS transcription. Doxorubicin strongly induces p53 and p73 binding to the NIS promoter, leading to an increased expression of endogenous NIS mRNA and protein in HCC and CCA cells, but not in PHH. Silencing NIS expression reduced doxorubicin-induced apoptosis in HCC cells, pointing to a possible role of a p53-family-dependent expression of NIS in apoptotic cell death. Altogether, these results indicate that the NIS gene is a direct target of the p53 family and suggests that the modulation of NIS by DNA-damaging agents is potentially exploitable to boost NIS upregulation in vivo.
Highlights
NIS-mediated ability of thyroid cancer cells to accumulate iodide is exploited for diagnostic nuclear imaging and radioiodine therapy.[6,7] NIS expression in thyroid cancers decreases as the cancer cell differentiation decreases,[5] rendering non-differentiated thyroid cancers refractory to radioiodine therapy
NIS expression was stimulated by retinoic acid (RA), estrogen and glucocorticoids, and it was induced through the Rac1/p38b mitogen-activated protein kinase (MAPK), cAMP and phosphoinositide-3 kinase (PI3K)-signaling pathways.[11,12,13,14]
We have shown that DNA damage triggers a transcriptional activation of NIS in liver cancer cells that is mediated by p53 and p53-related proteins, and suggests that NIS could be involved in DNA damage-induced apoptosis
Summary
NIS-mediated ability of thyroid cancer cells to accumulate iodide is exploited for diagnostic nuclear imaging and radioiodine therapy.[6,7] NIS expression in thyroid cancers decreases as the cancer cell differentiation decreases,[5] rendering non-differentiated thyroid cancers refractory to radioiodine therapy. Binding of Sp1 and a ‘Sp1-like protein’ to the GC-box is required for a basal activity of NIS promoter.[26] A RA-response element located at position À 1375 relative to NIS start codon mediates the activation of NIS expression by tRA in human follicular thyroid carcinoma cells.[27] NIS regulation by retinoids in breast cancer cells is effected through a downstream intronic enhancer, which binds RARa and RXR.[28,29,30,31,32,33] the cardiac homeobox transcription factor Nkx2.5, which is induced upon tRA stimulation, binds two cis-acting elements in the hNIS promoter located at À 446 and À 154 relative to ATG.[34]. We show that NIS gene is a direct target of the p53-family proteins and that DNA damage triggers NIS gene activation through a differential binding of p53 and p53-related proteins to NIS proximal promoter
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