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

Besides its established functions in intermediary metabolism and developmental processes, the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) has a less defined role in tumorigenesis. In the present study, we have identified a function for PPAR beta/delta in cancer cell invasion. We show that two structurally divergent inhibitory ligands for PPAR beta/delta, the inverse agonists ST247 and DG172, strongly inhibit the serum- and transforming growth factor beta (TGF beta)-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 PPAR beta/delta target in MDA-MB-231 cells, previously implicated in TGF beta-mediated tumor progression and metastatic dissemination. We show that the induction of ANGPTL4 by TGF beta and other oncogenic signals is strongly repressed by ST247 and DG172 in a PPAR beta/delta-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 PPAR beta/delta 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 PPAR beta/delta-ANGPTL4 pathway is involved in the regulation of tumor cell invasion and that its pharmacological manipulation by inverse PPAR beta/delta agonists is feasible.