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The nuclear corepressor NCoR is an essential mediator of the anti-tumorigenic and anti-metastatic actions of the thyroid hormone receptor β

AuthorsMartínez-Iglesias, Olaia ; Martin-Orozco, Rosa; Alonso-Merino, Elvira; Velasco-Martín, Juan P.; Regadera, Javier; Palacios, José; González-Peramato, Pilar; Aranda, Ana
Issue Date2014
CitationETA 2014
AbstractReduced expression or activity of the thyroid hormone receptors (TRs) are common events in cancer, suggesting that they could act as tumor suppressors. We have previously shown that TRb expression in SK-hep1 hepatocarcinoma cells (SK-TRb cells) reduces tumor growth, invasion, extravasation, and metastasis formation in nude mice. These effects are associated with a decreased expression of prometastatic genes. We found that the levels of the corepressor NCoR were increased in SK-TRb cells with respect to the parental cells. NCoR silencing reversed significantly the repressive effect of TRb on cellular invasion in matrigel assays and on prometastatic gene expression. Promoter activity of various prometastatic genes was also reduced by NCoR over-expression and enhanced after NCoR knock-down. Furthermore, in chromatin immunoprecipitation (ChIP) assays we observed increased recruitment of NCoR and repressive marks to these promoters in SK-TRb cells, demonstrating the important repressive effect of NCoR on prometastatic gene expression. NCoR expression was higher in tumor xenografts originated by SK-TRb cells than by parental cells and NCoR silencing also obliterated significantly the effect of TRb expression in vivo, reversing the inhibitory effect of the receptor on tumor growth. The reduced tumor infiltration found in TR?-expressing tumors was also abolished in NCoR-depleted cells and there was a tight inverse correlation between NCoR expression and transcripts levels of prometastatic genes. Tumor cell extravasation was also higher in NCoR depleted cells, and the inhibitory effect of TRb on metastasis formation was reversed. These changes were associated with increased expression of prometastatic genes in the metastatic lesions. Finally, NCoR and TRb expression was lower in human hepatocarcinomas tumors than in normal liver. These results demonstrate the essential role of NCoR in the anti-tumorigenic and anti-metastasic actions of TRb, and suggest the importance of the corepressor as a potential therapeutic target in cancer.
DescriptionResumen del trabajo presentado al 38th Annual Meeting of the European Thyroid Association celebrado en Santiago de Compostela (España) del 6 al 10 de septiembre de 2014.
Appears in Collections:(IIBM) Comunicaciones congresos
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