PPARd elicits ligand-independent repression of trefoil factor family to limit prostate cancer growth

Natalia Martín-Martín, Amaia Zabala-Letona, Sonia Fernandez-Ruiz, Leire Arreal, Laura Camacho, Mireia Castillo-Martin, Ana R. Cortazar, Veronica Torrano, Ianire Astobiza, Patricia Zuñiga-García, Aitziber Ugalde-Olano, Ana Loizaga-Iriarte, Miguel Unda, Lorea Valcarcel-Jim enez, Amaia Arruabarrena-Aristorena, Marco Piva, Pilar Sanchez-Mosquera, Ana M. Aransay, Antonio Gomez-Muñoz, Rosa BarrioJames D. Sutherland, Arkaitz Carracedo

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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. 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 PPARb/d in cancer is dictated by ligand-mediated activation.

Original languageEnglish
Pages (from-to)399-409
Number of pages11
JournalCancer Research
Issue number2
StatePublished - 15 Jan 2018
Externally publishedYes


Dive into the research topics of 'PPARd elicits ligand-independent repression of trefoil factor family to limit prostate cancer growth'. Together they form a unique fingerprint.

Cite this