Tumor Suppressor Action of Liganded Thyroid Hormone Receptor β by Direct Repression of β-Catenin Gene Expression

The abundance of beta-catenin, which plays a critical role in oncogenesis, is tightly controlled by proteasomal pathways. Its aberrant accumulation is associated with the overactivation of its oncogenic signaling and tumorigenesis in cancers, including thyroid cancer. Our previous studies have suggested that beta-catenin abundance could also be regulated at the transcriptional level by thyroid hormone (T(3)) and thyroid hormone receptor beta (TR beta). By using hypothyroid mice supplemented or not with T(3), we showed that T(3) significantly repressed Ctnnb1 expression in vivo in the thyroid. By using two human cell lines, i.e., the thyroid HTori and the cervical cancer HeLa cell lines, each stably expressing TR beta, we observed that T(3) induced the down-regulation of CTNNB1 transcript levels. Luciferase reporter assays with various constructs harboring 5' deletion of the CTNNB1 promoter or with mutated thyroid hormone response element (TRE) binding sites, and EMSAs showed that this transrepression was mediated through an interaction between TR beta-retinoid X receptor beta complexes and TREs located in the human CTNNB1 promoter between -807 and -772 and consisting of two hexamers separated by 14 nucleotides. The direct regulation of CTNNB1 expression by TR beta was further confirmed by chromatin immunoprecipitation assays showing TR beta recruitment to the CTNNB1 promoter in thyroid cells. This is the first report demonstrating a direct repression of the beta-catenin gene by liganded TR beta through interaction with negative TREs located in CTNNB1 promoter. Importantly, this study uncovers a new molecular mechanism whereby liganded TR beta acts as a tumor suppressor via inhibition of the expression of a potent tumor promoter, the CTNNB1 gene. (Endocrinology 151: 5528-5536, 2010)