Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion.

2.50
Hdl Handle:
http://hdl.handle.net/10033/306656
Title:
Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion.
Authors:
Adhikary, T; Brandt, D T; Kaddatz, K; Stockert, J; Naruhn, S; Meissner, W; Finkernagel, F; Obert, J; Lieber, S; Scharfe, M; Jarek, M; Toth, P M; Scheer, F; Diederich, W E; Reinartz, S; Grosse, R; Müller-Brüsselbach, S; Müller, R
Abstract:
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.
Affiliation:
Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
Citation:
Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion. 2013, 32 (44):5241-52 Oncogene
Journal:
Oncogene
Issue Date:
31-Oct-2013
URI:
http://hdl.handle.net/10033/306656
DOI:
10.1038/onc.2012.549
PubMed ID:
23208498
Type:
Article
Language:
en
ISSN:
1476-5594
Appears in Collections:
publications of the research group genomeanalytics (GMAK)

Full metadata record

DC FieldValue Language
dc.contributor.authorAdhikary, Ten
dc.contributor.authorBrandt, D Ten
dc.contributor.authorKaddatz, Ken
dc.contributor.authorStockert, Jen
dc.contributor.authorNaruhn, Sen
dc.contributor.authorMeissner, Wen
dc.contributor.authorFinkernagel, Fen
dc.contributor.authorObert, Jen
dc.contributor.authorLieber, Sen
dc.contributor.authorScharfe, Men
dc.contributor.authorJarek, Men
dc.contributor.authorToth, P Men
dc.contributor.authorScheer, Fen
dc.contributor.authorDiederich, W Een
dc.contributor.authorReinartz, Sen
dc.contributor.authorGrosse, Ren
dc.contributor.authorMüller-Brüsselbach, Sen
dc.contributor.authorMüller, Ren
dc.date.accessioned2013-12-10T13:01:17Z-
dc.date.available2013-12-10T13:01:17Z-
dc.date.issued2013-10-31-
dc.identifier.citationInverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion. 2013, 32 (44):5241-52 Oncogeneen
dc.identifier.issn1476-5594-
dc.identifier.pmid23208498-
dc.identifier.doi10.1038/onc.2012.549-
dc.identifier.urihttp://hdl.handle.net/10033/306656-
dc.description.abstractBesides 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.en
dc.language.isoenen
dc.rightsArchived with thanks to Oncogeneen
dc.titleInverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion.en
dc.typeArticleen
dc.contributor.departmentInstitute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.en
dc.identifier.journalOncogeneen

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