Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion
| Autor: | Maren Scharfe, Sabine Müller-Brüsselbach, Sonja Lieber, Silke Reinartz, Kerstin Kaddatz, Josefine Stockert, Philipp M. Toth, Till Adhikary, Michael Jarek, Dominique T. Brandt, Florian Finkernagel, Wolfgang Meissner, Frithjof Martin Scheer, Robert Grosse, J Obert, Rolf Müller, Simone Naruhn, Wibke E. Diederich |
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| Přispěvatelé: | Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany. |
| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
peroxisome proliferator-activated receptor β/δ (PPARβ/δ) Thiophenes Biology medicine.disease_cause angiopoietin-like 4 (ANGPTL4) Histone Deacetylases Piperazines ChIP-Seq Growth factor receptor Transcriptional repressor complex Cell Movement Transforming Growth Factor beta Cell Line Tumor transcriptional repression Genetics medicine Angiopoietin-Like Protein 4 Humans Neoplasm Invasiveness PPAR delta Molecular Biology Transcription Initiation Genetic Sulfonamides Binding Sites Acrylonitrile Transforming growth factor beta invasion Molecular biology Cell biology Gene Expression Regulation Neoplastic Retinoid X Receptors Nuclear receptor biology.protein Peroxisome proliferator-activated receptor delta Original Article transforming growth factor β (TGFβ) Signal transduction Carcinogenesis Angiopoietins Transforming growth factor Signal Transduction |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 |
| Popis: | Besides its established functions in intermediary metabolism and developmental processes, the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) has a less defined role in tumorigenesis. In the present study, we have identified a function for PPARβ/δ in cancer cell invasion. We show that two structurally divergent inhibitory ligands for PPARβ/δ, the inverse agonists ST247 and DG172, strongly inhibit the serum- and transforming growth factor β (TGFβ)-induced invasion of MDA-MB-231 human breast cancer cells into a three-dimensional matrigel matrix. To elucidate the molecular basis of this finding, we performed chromatin immunoprecipitation sequencing (ChIP-Seq) and microarray analyses, which identified the gene encoding angiopoietin-like 4 (ANGPTL4) as the major transcriptional PPARβ/δ target in MDA-MB-231 cells, previously implicated in TGFβ-mediated tumor progression and metastatic dissemination. We show that the induction of ANGPTL4 by TGFβ and other oncogenic signals is strongly repressed by ST247 and DG172 in a PPARβ/δ-dependent fashion, resulting in the inhibition of ANGPTL4 secretion. This effect is attributable to these ligands' ability to induce a dominant transcriptional repressor complex at the site of transcription initiation that blocks preinitiation complex formation through an histone deacetylase-independent, non-canonical mechanism. Repression of ANGPTL4 transcription by inverse PPARβ/δ agonists is functionally linked to the inhibition of cancer cell invasion into a three-dimensional matrix, as (i) invasion of MDA-MB-231 cells is critically dependent on ANGPTL4 expression, (ii) recombinant ANGPTL4 stimulates invasion, and (iii) reverses the inhibitory effect of ST247 and DG172. These findings indicate that a PPARβ/δ-ANGPTL4 pathway is involved in the regulation of tumor cell invasion and that its pharmacological manipulation by inverse PPARβ/δ agonists is feasible. |
| Databáze: | OpenAIRE |
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