Abstract
The nuclear receptor PPAR-β/δ (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. PPARD was 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 function of PPARD and understanding of the pathogenic molecular pathways elicited by this nuclear receptor.Significance: These findings challenge the presumption that the function of the nuclear receptor PPARβ/δ in cancer is dictated by ligand-mediated activation. Cancer Res; 78(2); 399-409. ©2017 AACR.
Highlights
In the process of cellular transformation, cancer cells exhibit profound changes in nutrient uptake and utilization as a way to generate substrates for the production of biomass
PPARd inhibits prostate cancer aggressiveness In order to elucidate the contribution of PPARd to prostate cancer biology, we first undertook an in vivo approach
Our results strongly suggest that the tumor suppressive activity of PPARd in prostate cancer relies on an unprecedented ligandindependent function of the nuclear receptor
Summary
In the process of cellular transformation, cancer cells exhibit profound changes in nutrient uptake and utilization as a way to generate substrates for the production of biomass. This metabolic switch in cancer cells involves rewiring of cellular signaling and reprogramming of metabolic pathways. One of the main triggers for metabolic reprogramming is the alteration in cancer genes that remodel the signaling landscape [1]. Seminal investigations have demonstrated that most cancer cells reprogram their metabolism to increase glucose uptake for glycolysis and decrease the. This study demonstrates for the first time that genetic events such as PGC1a alteration can trigger metabolic reprogramming in prostate cancer. The contribution of fatty acid oxidation (FAO) pathways to the pathogenesis and progression of prostate cancer remained obscure
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