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.
Source: Inverse
PPARβ/δ agonists suppress
oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion.
Adhikary T, Brandt DT, Kaddatz K, Stockert J, Naruhn S, Meissner W, Finkernagel
F, Obert J, Lieber S, Scharfe M, Jarek M, Toth PM, Scheer F, Diederich WE,
Reinartz S, Grosse R, Müller-Brüsselbach S, Müller R (rmueller@imt.uni-marburg.de).
Oncogene. 2012 Dec 3.
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