PPARβ activation inhibits melanoma cell proliferation involving repression of the Wilms' tumour suppressor WT1

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that strongly influence molecular signalling in normal and cancer cells. Although increasing evidence suggests a role of PPARs in skin carcinogenesis, only expression of PPAR gamma has been investigated in human melanoma tissues. Activation of PPAR alpha has been shown to inhibit the metastatic potential, whereas stimulation of PPAR gamma decreased melanoma cell proliferation. We show here that the third member of the PPAR family, PPAR beta/delta is expressed in human melanoma samples. Specific pharmacological activation of PPAR beta using GW0742 or GW501516 in low concentrations inhibits proliferation of human and murine melanoma cells. Inhibition of proliferation is accompanied by decreased expression of the Wilms' tumour suppressor 1 (WT1), which is implicated in melanoma proliferation. We demonstrate that PPAR beta directly represses WT1 as (1) PPAR beta activation represses WT1 promoter activity; (2) in chromatin immunoprecipitation and electrophoretic mobility shift assays, we identified a binding element for PPAR beta in the WT1 promoter; (3) deletion of this binding element abolishes repression by PPAR beta and (4) the WT1 downstream molecules nestin and zyxin are down-regulated upon PPAR beta activation. Our findings elucidate a novel mechanism of signalling by ligands of PPAR beta, which leads to suppression of melanoma cell growth through direct repression of WT1.