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¹ Department of Pharmaco-Biology² Centro Sanitario³ Department of Cellular Biology⁴ Faculty of Pharmacy, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy

(Correspondence should be addressed to S Andò; Email: sebastiano.ando{at}unical.it)

Peroxisome proliferator-activated receptor (PPAR) has been demonstrated to be anti-neoplastic against various human tumors. The aim of this study was to delineate the molecular mechanism underlying PPAR ligand rosiglitazone (BRL) antiproliferative effects in follicular WRO and anaplastic FRO human thyroid carcinoma cells. BRL upregulated the p21^Cip1/WAF1 levels in the two thyroid cancer cells, while did not modify the p53 protein content. Different evidences indicate that the p21^Cip1/WAF1 upregulation by BRL requires a functional PPAR, since it was reversed by silencing PPAR and pretreatment with GW9662, an irreversible PPAR antagonist. Transient transfection assays showed that BRL triggered the transcriptional activity of p21^Cip1/WAF1 promoter gene in a p53-independent way, being a p21^Cip1/WAF1 promoter construct deleted in the p53 sites still activated by BRL. The Sp1 inhibitor mithramycin silenced the p21^Cip1/WAF1 promoter activity suggesting an important role of Sp1 in mediating BRL activation. The electrophoretic mobility shift and chromatin immunoprecipitation (ChIP) assays evidenced a functional interaction between PPAR and Sp1 in regulating p21^Cip1/WAF1. Intriguingly, ChIP analysis revealed in the p21^Cip1/WAF1 gene promoter an increased recruitment of the RNA Pol II associated with an increased histone H3 acetylation and a reduced H3 methylation. The biological event, consistent with PPAR-induced WRO and FRO cell growth inhibition, was reversed by p21^Cip1/WAF1 antisense oligonucleotides and was confirmed by increasing the PPAR expression, suggesting a crucial role exerted by p21^Cip1/WAF1 in PPAR action. Our results further candidate BRL as a potential agent able to inhibit tumor progression of follicular and anaplastic thyroid carcinoma.

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