PPARδ elicits ligand-independent repression of Trefoil Factor Family to limit prostate cancer growth.

The nuclear receptor PPAR-b/d (PPARD) has essential roles in
fatty acid catabolism and energy homeostasis as well as cell
differentiation, inflammation, and metabolism. However, its contributions
to tumorigenesis are uncertain and have been disputed.
Here, we provide evidence of tumor suppressive activity of PPARD
in prostate cancer through a noncanonical and ligand-independent
pathway. PPARDwas downregulated in prostate cancer specimens.
In murine prostate epithelium, PPARD gene deletion resulted in
increased cellularity. Genetic modulation of PPARD in human
prostate cancer cell lines validated the tumor suppressive activity of
this gene in vitro and in vivo. Mechanistically, PPARD exerted its
activity in a DNA binding-dependent and ligand-independent
manner. We identified a novel set of genes repressed by PPARD
that failed to respond to ligand-mediated activation. Among these
genes, we observed robust regulation of the secretory trefoil factor
family (TFF) members, including a causal and correlative association
of TFF1 with prostate cancer biology in vitro and in patient
specimens. Overall, our results illuminate the oncosuppressive
functionofPPARDandunderstanding of the pathogenicmolecular
pathways elicited by this nuclear receptor.
Significance: These findings challenge the presumption that
the function of the nuclear receptor PPARb/d in cancer is dictated
by ligand-mediated activation