ABSTRACT
The thyroid hormone receptor (TR) is a suppressor of ras-mediated responses. To characterize the receptor domains involved in this function, we analyzed a panel of TRß1 mutants for their ability to interfere with ras-driven cyclin D1 activation, formation of transformation foci and tumor growth in nude mice. Our results show that the domains and mechanisms responsible for the anti-transforming and anti-tumorigenic actions of the receptor are divergent from those operating in classical T3-dependent transcriptional activation. TRß1 mutants that do not bind coactivators and do not transactivate retained the capacity of suppressing cellular transformation and tumor growth, whereas selective mutations in the hinge region affecting corepressors recruitment abolished these actions, while preserving ligand-dependent transcription. There was a strict parallelism between anti-transforming activity of the various mutants and their ability to antagonize cyclin D1 stimulation by ras, indicating that transrepression mechanisms may have an important function in suppression of the transforming effects of the oncogene by TRß1. The inhibitory action of T3 on transformation was further enhanced after over-expression of corepressors, while corepressor depletion by means of small-interference RNA reversed significantly hormonal action. This shows an important functional role of endogenous corepressors in suppression of ras-mediated transformation and tumorigenesis by TRß1.
Subject(s)
Cell Transformation, Neoplastic/genetics , Co-Repressor Proteins/metabolism , Genes, ras , Protein Interaction Domains and Motifs , Thyroid Hormone Receptors beta/metabolism , Animals , Co-Repressor Proteins/genetics , Cyclin D1/metabolism , Hep G2 Cells , Humans , Mice , Mice, Nude , Mutation , RNA, Small Interfering/metabolism , Thyroid Hormone Receptors beta/genetics , Triiodothyronine/metabolismABSTRACT
Histone deacetylases (HDACs) remove the acetyl groups of lysine residues of histone tails leading to chromatin compaction and transcriptional repression. In addition, HDACs can also influence transcription-independent events such as mitosis or deoxyribonucleic acid (DNA) repair and deacetylate nonhistone proteins involved in cell proliferation and death, altering their function. Histone deacetylase inhibitors (HDACi) constitute a promising treatment for cancer therapy due to their low toxicity. HDACi have been shown to induce differentiation, cell-cycle arrest, and apoptosis and to inhibit migration, invasion, and angiogenesis in many cancer cell lines. In addition, these compounds inhibit tumor growth in animal models and show antitumor activity in patients. HDACi alone and in combination with a variety of anticancer drugs are being tested in clinical trials, showing significant anticancer activity both in hematological and solid tumors. SAHA (vorinostat, Zolinza) was the first HDACi approved by the US Food and Drug Administration to enter the clinical oncology market for treating cutaneous T-cell lymphoma (CTCL) and is being tested for other malignancies.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Neoplasms/drug therapy , Neoplasms/enzymology , Animals , Clinical Trials as Topic , Gene Expression/drug effects , HumansABSTRACT
Histone deacetylases (HDACs) remove the acetyl groups of lysine residues of histone tails leading to chromatin compaction and transcriptional repression. In addition, HDACs can also influence transcription-independent events such as mitosis or deoxyribonucleic acid (DNA) repair and deacetylate nonhistone proteins involved in cell proliferation and death, altering their function. Histone deacetylase inhibitors (HDACi) constitute a promising treatment for cancer therapy due to their low toxicity. HDACi have been shown to induce differentiation, cell-cycle arrest, and apoptosis and to inhibit migration, invasion, and angiogenesis in many cancer cell lines. In addition, these compounds inhibit tumor growth in animal models and show antitumor activity in patients. HDACi alone and in combination with a variety of anticancer drugs are being tested in clinical trials, showing significant anticancer activity both in hematological and solid tumors. SAHA (vorinostat, Zolinza) was the first HDACi approved by the US Food and Drug Administration to enter the clinical oncology market for treating cutaneous T-cell lymphoma (CTCL) and is being tested for other malignancies (AU)
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