title: Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion.
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.
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Adhikary
authors.forename: D T
authors.initials: DT
authors.lastname: Brandt
authors.forename: K
authors.initials: K
authors.lastname: Kaddatz
authors.forename: J
authors.initials: J
authors.lastname: Stockert
authors.forename: S
authors.initials: S
authors.lastname: Naruhn
authors.forename: W
authors.initials: W
authors.lastname: Meissner
authors.forename: F
authors.initials: F
authors.lastname: Finkernagel
authors.forename: J
authors.initials: J
authors.lastname: Obert
authors.forename: S
authors.initials: S
authors.lastname: Lieber
authors.forename: M
authors.initials: M
authors.lastname: Scharfe
authors.forename: M
authors.initials: M
authors.lastname: Jarek
authors.forename: P M
authors.initials: PM
authors.lastname: Toth
authors.forename: F
authors.initials: F
authors.lastname: Scheer
authors.forename: W E
authors.initials: WE
authors.lastname: Diederich
authors.forename: S
authors.initials: S
authors.lastname: Reinartz
authors.forename: R
authors.initials: R
authors.lastname: Grosse
authors.forename: S
authors.initials: S
authors.lastname: Müller-Brüsselbach
authors.forename: R
authors.initials: R
authors.lastname: Müller
mesh_terms: D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000494:pharmacology; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness; D047494:PPAR delta / Q000819:agonists / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology*; D047488:Retinoid X Receptors / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D061785:Transcription Initiation, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: C573844:2-(2-bromophenyl)-3-((4-(1-methylpiperazine)amino)phenyl)acrylonitrile; C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D047494:PPAR delta; D010879:Piperazines; D047488:Retinoid X Receptors; D013449:Sulfonamides; D013876:Thiophenes; D016212:Transforming Growth Factor beta; C585354:methyl 3-(N-(4-(hexylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate; D006655:Histone Deacetylases; D000181:Acrylonitrile