Tumor suppressor action of liganded thyroid hormone receptor beta by direct repression of beta-catenin gene expression.
The abundance of β-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 β-catenin abundance could also be regulated at the transcriptional level by thyroid hormone (T(3)) and thyroid hormone receptor β (TRβ). 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 TRβ, 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 TRβ-retinoid X receptor β 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 TRβ was further confirmed by chromatin immunoprecipitation assays showing TRβ recruitment to the CTNNB1 promoter in thyroid cells. This is the first report demonstrating a direct repression of the β-catenin gene by liganded TRβ through interaction with negative TREs located in CTNNB1 promoter. Importantly, this study uncovers a new molecular mechanism whereby liganded TRβ acts as a tumor suppressor via inhibition of the expression of a potent tumor promoter, the CTNNB1 gene.
Guigon
Celine J
CJ
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, Bethesda, Maryland 20892-4264, USA.
Kim
Dong Wook
DW
Zhu
Xuguang
X
Zhao
Li
L
Cheng
Sheue-yann
SY
D000704:Analysis of Variance; D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism* / Q000494:pharmacology; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
D037042:Thyroid Hormone Receptors beta; D051176:beta Catenin; D014284:Triiodothyronine