ABSTRACT
TGF-ß, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-ß/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMAD-binding elements in response to TGF-ß, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases.
Subject(s)
Liver Cirrhosis/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Triiodothyronine/metabolism , Animals , Bleomycin/adverse effects , Bleomycin/pharmacology , Carbon Tetrachloride Poisoning/genetics , Carbon Tetrachloride Poisoning/metabolism , Carbon Tetrachloride Poisoning/pathology , Liver Cirrhosis/chemically induced , Liver Cirrhosis/genetics , Liver Cirrhosis/pathology , Mice , Mice, Knockout , Smad3 Protein/genetics , Smad3 Protein/metabolism , Smad4 Protein/genetics , Smad4 Protein/metabolism , Transforming Growth Factor beta/genetics , Triiodothyronine/geneticsABSTRACT
Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor ß1 (TRß) appears to be associated with cancer onset and progression. We found that expression of TRß increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRß. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies.
Subject(s)
Homeostasis , Nuclear Receptor Co-Repressor 1/genetics , Aged , Animals , Breast Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation , DNA Methylation/genetics , Epigenesis, Genetic , Female , Gene Expression Regulation, Neoplastic , Gene Silencing , Heterochromatin/metabolism , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Mice, Nude , Middle Aged , Neoplasm Invasiveness , Neoplasm Metastasis , Nuclear Receptor Co-Repressor 1/metabolism , Nuclear Receptor Co-Repressor 2/metabolism , Promoter Regions, Genetic/genetics , RNA, Small Interfering/metabolism , Thyroid Hormone Receptors beta , Xenograft Model Antitumor AssaysABSTRACT
Heterodimers of the retinoid X receptor (RXR) with the thyroid hormone receptor (TR) are considered to be nonpermissive. It is believed that within these complexes RXR acts as a "silent partner." We demonstrate here that a permissive heterodimer mediates stimulation of prolactin expression by the thyroid hormone T3 and by 9-cis retinoic acid (9-cis-RA). A response element located in the prolactin distal enhancer mediates transactivation by both ligands in pituitary cells, and RXR recruits coactivators when bound to this element as a heterodimer with TR. Furthermore, transcription by the RXR agonist can be obtained in CV-1 cells only after overexpression of coactivators, and overexpression of corepressors inhibits the response in pituitary cells. Thus, cell type-specific differences in coregulator recruitment can determine the cellular response to both ligands. Coactivator recruitment by 9-cis-RA requires the ligand-dependent transactivation domains (AF-2) of both heterodimeric partners. Interestingly, the presence of the RXR ligand can overcome the deleterious effect of the AF-2 mutation E401Q on association with coactivators and transactivation. These results demonstrate an unexpected role for RXR in TR signaling and show that in particular cellular environments this receptor can act as a "nonsilent" partner of TR, allowing stimulation by RXR agonists.
